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Entry
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- *609806 - HYDROXYMETHYLBILANE SYNTHASE; HMBS
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*609806</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<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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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/609806">Table View</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000256269;t=ENST00000652429" 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=3145" 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=609806" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000256269;t=ENST00000652429" 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_000190,NM_001024382,NM_001258208,NM_001258209,NM_001425052,NM_001425053,NM_001425054,NM_001425056,NM_001425057,NM_001425058,NM_001425059,NM_001425061,NM_001425062,NM_001425063,NM_001425065,XM_011542796,XM_017017629" 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_000190" 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=609806" 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=01440&isoform_id=01440_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/HMBS" 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/35305,35307,35309,189644,292385,292386,300290,974448,974449,1170217,4433210,12653497,14198180,17939638,20149500,51241768,66933009,113707391,119587851,119587852,119587853,119587854,158261573,206725173,323387859,384551654,384551656,610770464,767970087,1034573305,2462524838,2462524842,2596092751,2596092753,2596092757,2596092759,2596092761,2596092765,2596092767,2596092771,2596092773,2596092779,2596092781" 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/P08397" 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=3145" 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=ENSG00000256269;t=ENST00000652429" 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=HMBS" 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=HMBS" 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+3145" 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/HMBS" 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:3145" 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/3145" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr11&hgg_gene=ENST00000652429.1&hgg_start=119084881&hgg_end=119093549&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:4982" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:4982" 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/hmbs" 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=609806[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=609806[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/ENSG00000256269" 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=HMBS" 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=HMBS" 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=HMBS" 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=HMBS&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/PA29317" 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:4982" 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/FBgn0010786.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:96112" 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/HMBS#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:96112" 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/3145/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA001493/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=3145" 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-040426-1375" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:3145" 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=HMBS&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> 234422006<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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609806
|
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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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HYDROXYMETHYLBILANE SYNTHASE; HMBS
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</span>
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</h3>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
|
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</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
PORPHOBILINOGEN DEAMINASE; PBGD<br />
|
|
PRE-UROPORPHYRINOGEN SYNTHASE<br />
|
|
UROPORPHYRINOGEN I SYNTHASE<br />
|
|
UROPORPHYRINOGEN I SYNTHETASE
|
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</span>
|
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</h4>
|
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</div>
|
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</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
|
<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=HMBS" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">HMBS</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/11/1004?start=-3&limit=10&highlight=1004">11q23.3</a>
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr11:119084881-119093549&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">11:119,084,881-119,093,549</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>
|
|
<br />
|
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</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=620704,620711,176000,176000" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/11/1004?start=-3&limit=10&highlight=1004">
|
|
11q23.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Encephalopathy, porphyria-related
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/620704"> 620704 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
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<span class="mim-font">
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PheneGene Graphics <span class="caret"></span>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>Porphobilinogen deaminase (PBGD; <a href="https://enzyme.expasy.org/EC/4.3.1.8" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 4.3.1.8</a>) is the third enzyme of the biosynthetic pathway leading to the production of heme. It catalyzes the synthesis of hydroxymethylbilane by stepwise condensation of 4 porphobilinogen units. Hydroxymethylbilane is then converted to uroporphyrinogen III by uroporphyrinogen III synthetase (UROS; <a href="/entry/606938">606938</a>) (<a href="#49" class="mim-tip-reference" title="Raich, N., Romeo, P. H., Dubart, A., Beaupain, D., Cohen-Solal, M., Goossens, M. <strong>Molecular cloning and complete primary sequence of human erythrocyte porphobilinogen deaminase.</strong> Nucleic Acids Res. 14: 5955-5968, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2875434/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2875434</a>] [<a href="https://doi.org/10.1093/nar/14.15.5955" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2875434">Raich et al., 1986</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2875434" 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="#49" class="mim-tip-reference" title="Raich, N., Romeo, P. H., Dubart, A., Beaupain, D., Cohen-Solal, M., Goossens, M. <strong>Molecular cloning and complete primary sequence of human erythrocyte porphobilinogen deaminase.</strong> Nucleic Acids Res. 14: 5955-5968, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2875434/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2875434</a>] [<a href="https://doi.org/10.1093/nar/14.15.5955" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2875434">Raich et al. (1986)</a> isolated a cDNA clone corresponding to the human erythrocyte porphobilinogen deaminase gene from a human erythrocyte library prepared from human spleen. The deduced 334-amino acid protein has a calculated molecular mass of approximately 37.6 kD. Northern blot analysis identified a single 1.6-kb mRNA transcript. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2875434" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Grandchamp, B., de Verneuil, H., Beaumont, C., Chretien, S., Walter, O., Nordmann, Y. <strong>Tissue-specific expression of porphobilinogen deaminase: two isoenzymes from a single gene.</strong> Europ. J. Biochem. 162: 105-110, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3816774/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3816774</a>] [<a href="https://doi.org/10.1111/j.1432-1033.1987.tb10548.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3816774">Grandchamp et al. (1987)</a> determined that there are 2 PBGD isoforms that differ by approximately 2 kD (40 and 42 kD). One is active in all tissues and can be isolated from liver, and the other is restricted to erythrocytes. The nonerythrocyte isoform contains an additional 17 amino acid residues at the N terminus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3816774" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Chretien, S., Dubart, A., Beaupain, D., Raich, N., Grandchamp, B., Rosa, J., Goossens, M., Romeo, P.-H. <strong>Alternative transcription and splicing of the human porphobilinogen deaminase gene result either in tissue-specific or in housekeeping expression.</strong> Proc. Nat. Acad. Sci. 85: 6-10, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3422427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3422427</a>] [<a href="https://doi.org/10.1073/pnas.85.1.6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3422427">Chretien et al. (1988)</a> demonstrated that the PBGD gene undergoes alternative splicing with 2 different promoters to yield 2 mRNAs. The first 'upstream' promoter is active in all tissues and has structural features of a housekeeping promoter, whereas the second promoter, located 3 kb downstream, is active only in erythrocytes and shows structural homology to the beta-globin gene (<a href="/entry/141900">141900</a>) promoters. The 2 mRNAs differ only in their first exon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3422427" 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="Gubin, A. N., Miller, J. L. <strong>Human erythroid porphobilinogen deaminase exists in 2 splice variants.</strong> Blood 97: 815-817, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11157504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11157504</a>] [<a href="https://doi.org/10.1182/blood.v97.3.815" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11157504">Gubin and Miller (2001)</a> identified 2 alternatively spliced isoforms of erythroid PBGD in CD34+/- (<a href="/entry/142230">142230</a>) erythroid precursor cells. Complete sequencing showed that the alternatively spliced form, designated PBGD-EA, contained the intron between exons 2 and 3, thus extending the 5-prime untranslated region of the erythroid transcript by 176 bp. Northern blot analysis identified a distinct 1.5-kb mRNA corresponding to the alternatively spliced erythrocyte isoform only in bone marrow and fetal spleen. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11157504" 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="#4" class="mim-tip-reference" title="Chretien, S., Dubart, A., Beaupain, D., Raich, N., Grandchamp, B., Rosa, J., Goossens, M., Romeo, P.-H. <strong>Alternative transcription and splicing of the human porphobilinogen deaminase gene result either in tissue-specific or in housekeeping expression.</strong> Proc. Nat. Acad. Sci. 85: 6-10, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3422427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3422427</a>] [<a href="https://doi.org/10.1073/pnas.85.1.6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3422427">Chretien et al. (1988)</a> determined that the HMBS gene contains 15 exons and spans approximately 10 kb of DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3422427" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The housekeeping HMBS transcript contains exons 1 and 3-15; the erythroid HMBS transcript is encoded by exons 2-15 (<a href="#3" class="mim-tip-reference" title="Chen, C. H., Astrin, K. H., Lee, G., Anderson, K. E., Desnick, R. J. <strong>Acute intermittent porphyria: identification and expression of exonic mutations in the hydroxymethylbilane synthase gene: an initiation codon missense mutation in the housekeeping transcript causes 'variant acute intermittent porphyria' with normal expression of the erythroid-specific enzyme.</strong> J. Clin. Invest. 94: 1927-1937, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7962538/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7962538</a>] [<a href="https://doi.org/10.1172/JCI117543" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7962538">Chen et al., 1994</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7962538" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By study of mouse-human hybrid clones, Meisler et al. (<a href="#38" class="mim-tip-reference" title="Meisler, M. H., Wanner, L. A., Eddy, R. E., Shows, T. H. <strong>Uroporphyrinogen I synthase: chromosomal linkage and isozyme expression in human-mouse hybrid cells. (Abstract)</strong> Am. J. Hum. Genet. 32: 47A only, 1980."None>1980</a>, <a href="#39" class="mim-tip-reference" title="Meisler, M. H., Wanner, L., Kao, F. T., Jones, C. <strong>Localization of the uroporphyrinogen I synthase locus to human chromosome region 11q13-qter and interconversion of enzyme isomers.</strong> Cytogenet. Cell Genet. 31: 124-128, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7307577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7307577</a>] [<a href="https://doi.org/10.1159/000131637" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7307577">1981</a>) showed that PBG-deaminase is determined by a gene on chromosome 11; <a href="#56" class="mim-tip-reference" title="Wang, A.-L., Arredondo-Vega, F. X., Giampietro, P. F., Smith, M., Anderson, W. F., Desnick, R. J. <strong>Regional gene assignment of human porphobilinogen deaminase and esterase A(4) to chromosome 11q23-11qter.</strong> Proc. Nat. Acad. Sci. 78: 5734-5738, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6946513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6946513</a>] [<a href="https://doi.org/10.1073/pnas.78.9.5734" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6946513">Wang et al. (1981)</a> assigned the locus to the long arm in the segment 11q23-qter. In 3 children with trisomy of 11qter, <a href="#8" class="mim-tip-reference" title="de Verneuil, H., Phung, N., Nordmann, Y., Allard, D., Leprince, F., Jerome, H., Aurias, A., Rethore, M. O. <strong>Assignment of human uroporphyrinogen I synthase locus to region 11qter by gene dosage effect.</strong> Hum. Genet. 60: 212-213, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6985467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6985467</a>] [<a href="https://doi.org/10.1007/BF00303004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6985467">de Verneuil et al. (1982)</a> studied expression of uroporphyrinogen I synthase. Dosage effect supported assignment to the region 11q23.2-qter. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7307577+6946513+6985467" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By in situ hybridization and by gene dosage studies in patients with monosomy or trisomy of the terminal portion of 11q, <a href="#43" class="mim-tip-reference" title="Namba, H., Narahara, K., Tsuji, K., Yokoyama, Y., Seino, Y. <strong>Assignment of human porphobilinogen deaminase to 11q24.1-q24.2 by in situ hybridization and gene dosage studies.</strong> Cytogenet. Cell Genet. 57: 105-108, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1914516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1914516</a>] [<a href="https://doi.org/10.1159/000133123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1914516">Namba et al. (1991)</a> refined the assignment of the PBGD gene to 11q24.1-q24.2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1914516" 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="#54" class="mim-tip-reference" title="Tunnacliffe, A., McGuire, R. S. <strong>A physical linkage group in human chromosome band 11q23 covering a region implicated in leukocyte neoplasia.</strong> Genomics 8: 447-453, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1981047/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1981047</a>] [<a href="https://doi.org/10.1016/0888-7543(90)90030-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1981047">Tunnacliffe and McGuire (1990)</a> constructed a long-range restriction map extending over 1.8 Mb of 11q23.3 using pulsed field gel electrophoresis and concluded that PBGD is situated in the following relation to 5 other genes: cen--CD3E--CD3D--CD3G--PBGD--CBL2--THY1--qter. They determined that the CD3G (<a href="/entry/186740">186740</a>) gene and PBGD are separated by 750 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1981047" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By the method of isoelectric focusing, <a href="#37" class="mim-tip-reference" title="Meisler, M. H., Carter, M. L. C. <strong>Rare structural variants of human and murine uroporphyrinogen I synthase.</strong> Proc. Nat. Acad. Sci. 77: 2848-2852, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6930671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6930671</a>] [<a href="https://doi.org/10.1073/pnas.77.5.2848" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6930671">Meisler and Carter (1980)</a> identified structural variants of PBG-deaminase. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6930671" 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="#33" class="mim-tip-reference" title="Louie, G. V., Brownlie, P. D., Lambert, R., Cooper, J. B., Blundell, T. L., Wood, S. P., Warren, M. J., Woodcock, S. C., Jordan, P. M. <strong>Structure of porphobilinogen deaminase reveals a flexible multidomain polymerase with a single catalytic site.</strong> Nature 359: 33-39, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1522882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1522882</a>] [<a href="https://doi.org/10.1038/359033a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1522882">Louie et al. (1992)</a> defined the 3-domain structure of PBGD by x-ray analysis. Two of the domains structurally resembled the transferrins (see, e.g., TF; <a href="/entry/190000">190000</a>). The x-ray structure and results from site-directed mutagenesis provided evidence for a single catalytic site. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1522882" 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><strong><em>Autosomal Dominant Acute Intermittent Porphyria</em></strong></p><p>
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In a large Dutch family with the nonerythroid variant of acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#16" class="mim-tip-reference" title="Grandchamp, B., Picat, C., Mignotte, V., Wilson, J. H. P., te Velde, K., Sandkuyl, L., Romeo, P. H., Goossens, M., Nordmann, Y. <strong>Tissue-specific splicing mutation in acute intermittent porphyria.</strong> Proc. Nat. Acad. Sci. 86: 661-664, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2563167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2563167</a>] [<a href="https://doi.org/10.1073/pnas.86.2.661" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2563167">Grandchamp et al. (1989)</a> identified a heterozygous splice site mutation in intron 1 of the PBGD gene (<a href="#0001">609806.0001</a>). The mutation interrupted the sequence coding for the nonerythroid isoform of PBGD; thus, expression of the erythroid isoform was unaffected. In a patient with CRM-positive AIP, <a href="#14" class="mim-tip-reference" title="Grandchamp, B., Picat, C., de Rooij, F., Beaumont, C., Wilson, P., Deybach, J. C., Nordmann, Y. <strong>A point mutation G-to-A in exon 12 of the porphobilinogen deaminase gene results in exon skipping and is responsible for acute intermittent porphyria.</strong> Nucleic Acids Res. 17: 6637-6649, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2789372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2789372</a>] [<a href="https://doi.org/10.1093/nar/17.16.6637" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2789372">Grandchamp et al. (1989)</a> identified a heterozygous mutation in the HMBS gene, resulting in the skipping of exon 12 (<a href="#0002">609806.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2789372+2563167" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of 11 different families with either CRM-negative or CRM-positive AIP, <a href="#13" class="mim-tip-reference" title="Grandchamp, B., Delfau, M. H., Picat, C., de Rooij, F. W. M., Nordmann, Y. <strong>Heterogeneity of the molecular defects in acute intermittent porphyria. (Abstract)</strong> Am. J. Hum. Genet. 47 (suppl.): A156 only, 1990."None>Grandchamp et al. (1990)</a> identified 7 different point mutations in the PBGD gene.</p><p>In a patient with the nonerythroid variant of AIP, <a href="#3" class="mim-tip-reference" title="Chen, C. H., Astrin, K. H., Lee, G., Anderson, K. E., Desnick, R. J. <strong>Acute intermittent porphyria: identification and expression of exonic mutations in the hydroxymethylbilane synthase gene: an initiation codon missense mutation in the housekeeping transcript causes 'variant acute intermittent porphyria' with normal expression of the erythroid-specific enzyme.</strong> J. Clin. Invest. 94: 1927-1937, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7962538/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7962538</a>] [<a href="https://doi.org/10.1172/JCI117543" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7962538">Chen et al. (1994)</a> identified a mutation in the initiation codon of the housekeeping HMBS isoform (M1V; <a href="#0044">609806.0044</a>). <a href="#48" class="mim-tip-reference" title="Puy, H., Gross, U., Deybach, J. C., Robreau, A. M., Frank, M., Nordmann, Y., Doss, M. <strong>Exon 1 donor splice site mutations in the porphobilinogen deaminase gene in the non-erythroid variant form of acute intermittent porphyria.</strong> Hum. Genet. 103: 570-575, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9860299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9860299</a>] [<a href="https://doi.org/10.1007/s004390050871" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9860299">Puy et al. (1998)</a> identified 3 different mutations in the donor splice site of the HMBS gene in 4 unrelated patients with the nonerythroid variant of AIP. They found that the splice site mutations resulted in activation of a cryptic splice site located 67 nucleotides downstream from the normal splice site, leading to a frameshift and premature stop codon in exon 4. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7962538+9860299" 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 28 Finnish families representing 72% of all AIP families in the Finnish population of 5 million, <a href="#23" class="mim-tip-reference" title="Kauppinen, R., Mustajoki, S., Pihlaja, H., Peltonen, L., Mustajoki, P. <strong>Acute intermittent porphyria in Finland: 19 mutations in the porphobilinogen deaminase gene.</strong> Hum. Molec. Genet. 4: 215-222, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7757070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7757070</a>] [<a href="https://doi.org/10.1093/hmg/4.2.215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7757070">Kauppinen et al. (1995)</a> found 19 separate mutations in HMBS: 13 novel mutations, including 1 de novo event, and 6 previously characterized mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7757070" 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="#58" class="mim-tip-reference" title="Whatley, S. D., Woolf, J. R., Elder, G. H. <strong>Comparison of complementary and genomic DNA sequencing for the detection of mutations in the HMBS gene in British patients with acute intermittent porphyria: identification of 25 novel mutations.</strong> Hum. Genet. 104: 505-510, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10453740/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10453740</a>] [<a href="https://doi.org/10.1007/s004390050995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10453740">Whatley et al. (1999)</a> found 39 different mutations in the HMBS gene in 54 of 57 consecutive patients with AIP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10453740" 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 patients with the nonerythroid variant of AIP, <a href="#57" class="mim-tip-reference" title="Whatley, S. D., Roberts, A. G., Llewellyn, D. H., Bennett, C. P., Garrett, C., Elder, G. H. <strong>Non-erythroid form of acute intermittent porphyria caused by promoter and frameshift mutations distant from the coding sequence of exon 1 of the HMBS gene.</strong> Hum. Genet. 107: 243-248, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11071386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11071386</a>] [<a href="https://doi.org/10.1007/s004390000356" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11071386">Whatley et al. (2000)</a> identified mutations in the housekeeping promoter (-154delG; <a href="#0041">609806.0041</a>) and in exon 3 (41delA; <a href="#0042">609806.0042</a>) of the HMBS gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11071386" 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="#11" class="mim-tip-reference" title="Floderus, Y., Shoolingin-Jordan, P. M., Harper, P. <strong>Acute intermittent porphyria in Sweden. Molecular, functional and clinical consequences of some new mutations found in the porphobilinogen deaminase gene.</strong> Clin. Genet. 62: 288-297, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12372055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12372055</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2002.620406.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12372055">Floderus et al. (2002)</a> studied most of the AIP kindreds in Sweden. They identified 27 novel mutations in the HMBS gene, bringing the total number of known mutations in the HMBS gene in Sweden to 39. Most of the mutations were located in exons 10 and 12, with fewer in exon 7. <a href="#11" class="mim-tip-reference" title="Floderus, Y., Shoolingin-Jordan, P. M., Harper, P. <strong>Acute intermittent porphyria in Sweden. Molecular, functional and clinical consequences of some new mutations found in the porphobilinogen deaminase gene.</strong> Clin. Genet. 62: 288-297, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12372055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12372055</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2002.620406.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12372055">Floderus et al. (2002)</a> used the 3-dimensional structure of the porphobilinogen deaminase enzyme to predict the possible molecular and functional consequences of the novel Swedish missense and nonsense mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12372055" 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>Porphyria-Related Encephalopathy</em></strong></p><p>
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In a Dutch girl with porphyria-related encephalopathy (ENCEP; <a href="/entry/620704">620704</a>) originally reported by <a href="#2" class="mim-tip-reference" title="Beukeveld, G. J. J., Wolthers, B. G., Nordmann, Y., Deybach, J. C., Grandchamp, B., Wadman, S. K. <strong>A retrospective study of a patient with homozygous form of acute intermittent porphyria.</strong> J. Inherit. Metab. Dis. 13: 673-683, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2246851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2246851</a>] [<a href="https://doi.org/10.1007/BF01799566" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2246851">Beukeveld et al. (1990)</a>, <a href="#45" class="mim-tip-reference" title="Picat, C., Delfau, M. H., de Rooij, F. W. M., Beukeveld, G. J. J., Wolthers, B. G., Wadman, S. K., Nordmann, Y., Grandchamp, B. <strong>Identification of the mutations in the parents of a patient with a putative compound heterozygosity for acute intermittent porphyria.</strong> J. Inherit. Metab. Dis. 13: 684-686, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2246852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2246852</a>] [<a href="https://doi.org/10.1007/BF01799567" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2246852">Picat et al. (1990)</a> identified compound heterozygous missense mutations in the HMBS gene (R167Q, <a href="#0005">609806.0005</a> and R173Q, <a href="#0006">609806.0006</a>). Each parent who had classic AIP was heterozygous for 1 of the mutations. The patient had a severe disease course and died at 8 years of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2246851+2246852" 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 an English brother and sister with ENCEP, <a href="#31" class="mim-tip-reference" title="Llewellyn, D. H., Smyth, S. J., Elder, G. H., Hutchesson, A. C., Rattenbury, J. M., Smith, M. F. <strong>Homozygous acute intermittent porphyria: compound heterozygosity for adjacent base transitions in the same codon of the porphobilinogen deaminase gene.</strong> Hum. Genet. 89: 97-98, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1577472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1577472</a>] [<a href="https://doi.org/10.1007/BF00207051" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1577472">Llewellyn et al. (1992)</a> identified compound heterozygous missense mutations in the HMBS gene (R167Q and R167W, <a href="#0013">609806.0013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1577472" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#52" class="mim-tip-reference" title="Solis, C., Martinez-Bermejo, A., Naidich, T. P., Kaufmann, W. E., Astrin, K. H., Bishop, D. F., Desnick, R. J. <strong>Acute intermittent porphyria: studies of the severe homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias.</strong> Arch. Neurol. 61: 1764-1770, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15534187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15534187</a>] [<a href="https://doi.org/10.1001/archneur.61.11.1764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15534187">Solis et al. (2004)</a> reported a Spanish patient with ENCEP who was homozygous for the R167W substitution. Both parents were heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15534187" 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 patient, born of consanguineous Turkish parents, with ENCEP, <a href="#21" class="mim-tip-reference" title="Hessels, J., Voortman, G., van der Wagen, A., van der Elzen, C., Scheffer, H., Zuijderhoudt, F. M. J. <strong>Homozygous acute intermittent porphyria in a 7-year-old boy with massive excretions of porphyrins and porphyrin precursors.</strong> J. Inherit. Metab. Dis. 27: 19-27, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14970743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14970743</a>] [<a href="https://doi.org/10.1023/B:BOLI.0000016613.75677.05" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14970743">Hessels et al. (2004)</a> detected a homozygous missense mutation in the HMBS gene (L81P; <a href="#0045">609806.0045</a>). Porphobilinogen deaminase activity in red cells was decreased to 2 to 4%. The clinically unaffected parents were heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14970743" 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>Porphyria-Related Leukoencephalopathy</em></strong></p><p>
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In 3 adult sibs, born of unrelated Dutch parents, with slowly progressive porphyria-related leukoencephalopathy (LENCEP; <a href="/entry/620711">620711</a>), <a href="#25" class="mim-tip-reference" title="Kevelam, S. H., Neeleman, R. A., Waisfisz, Q., Friesema, E. C. H., Langendonk, J. G., van der Knaap, M. S. <strong>Acute intermittent porphyria-related leukoencephalopathy.</strong> Neurology 87: 1258-1265, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27558376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27558376</a>] [<a href="https://doi.org/10.1212/WNL.0000000000003129" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27558376">Kevelam et al. (2016)</a> identified compound heterozygous missense mutations in the HMBS gene: R167Q and R225Q (<a href="#0047">609806.0047</a>). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. At least 2 unaffected sibs carried a heterozygous R225Q variant. HMBS erythrocyte activity ranged from 55 to 67% of normal controls in the affected sibs, similar to heterozygous carriers of HMBS mutations. One unaffected sib had 83% activity and the other had 105% activity. <a href="#25" class="mim-tip-reference" title="Kevelam, S. H., Neeleman, R. A., Waisfisz, Q., Friesema, E. C. H., Langendonk, J. G., van der Knaap, M. S. <strong>Acute intermittent porphyria-related leukoencephalopathy.</strong> Neurology 87: 1258-1265, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27558376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27558376</a>] [<a href="https://doi.org/10.1212/WNL.0000000000003129" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27558376">Kevelam et al. (2016)</a> noted that both the R225Q and R167Q mutations had been reported in the heterozygous state in patients with autosomal dominant AIP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27558376" 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 45-year-old man (P3), born of unrelated Dutch parents (family 2), with LENCEP, <a href="#53" class="mim-tip-reference" title="Stutterd, C. A., Kidd, A., Florkowski, C., Janus, E., Fanjul, M., Raizis, A., Wu, T. Y., Archer, J., Leventer, R. J., Amor, D. J., Lukic, V., Bahlo, M., Gow, P., Lockhart, P. J., van der Knaap, M. S., Delatycki, M. B. <strong>Expanding the clinical and radiological phenotypes of leukoencephalopathy due to biallelic HMBS mutations.</strong> Am. J. Med. Genet. 185A: 2941-2950, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34089223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34089223</a>] [<a href="https://doi.org/10.1002/ajmg.a.62377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34089223">Stutterd et al. (2021)</a> identified compound heterozygosity for the R225Q and R167Q mutations. His mother, who was heterozygous for the R167Q mutation, had latent AIP; his father was unavailable for testing. A measurement of HMBS enzyme activity was not available for P3. <a href="#53" class="mim-tip-reference" title="Stutterd, C. A., Kidd, A., Florkowski, C., Janus, E., Fanjul, M., Raizis, A., Wu, T. Y., Archer, J., Leventer, R. J., Amor, D. J., Lukic, V., Bahlo, M., Gow, P., Lockhart, P. J., van der Knaap, M. S., Delatycki, M. B. <strong>Expanding the clinical and radiological phenotypes of leukoencephalopathy due to biallelic HMBS mutations.</strong> Am. J. Med. Genet. 185A: 2941-2950, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34089223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34089223</a>] [<a href="https://doi.org/10.1002/ajmg.a.62377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34089223">Stutterd et al. (2021)</a> noted that the pathogenicity of the R225Q variant had not been conclusively demonstrated and that previous functional studies had yielded conflicting results of the effect of this variant on HMBS enzyme activity. <a href="#53" class="mim-tip-reference" title="Stutterd, C. A., Kidd, A., Florkowski, C., Janus, E., Fanjul, M., Raizis, A., Wu, T. Y., Archer, J., Leventer, R. J., Amor, D. J., Lukic, V., Bahlo, M., Gow, P., Lockhart, P. J., van der Knaap, M. S., Delatycki, M. B. <strong>Expanding the clinical and radiological phenotypes of leukoencephalopathy due to biallelic HMBS mutations.</strong> Am. J. Med. Genet. 185A: 2941-2950, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34089223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34089223</a>] [<a href="https://doi.org/10.1002/ajmg.a.62377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34089223">Stutterd et al. (2021)</a> also identified a homozygous missense mutation in the HMBS gene (A84D; <a href="#0048">609806.0048</a>) in 2 adult sibs, born of consanguineous Lebanese parents (family 1), with slowly progressive LENCEP. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not present in the gnomAD database. Erythrocyte HMBS enzyme activity in the affected sibs ranged from 13 to 18% of normal control values. Erythrocyte HMBS activity in an unaffected sib who was heterozygous for the mutation was 50% of normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34089223" 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>During study of the pathogenesis of the neurologic symptoms of AIP, <a href="#29" class="mim-tip-reference" title="Lindberg, R. L. P., Porcher, C., Grandchamp, B., Ledermann, B., Burki, K., Brandner, S., Aguzzi, A., Meyer, U. A. <strong>Porphobilinogen deaminase deficiency in mice causes a neuropathy resembling that of human hepatic porphyria.</strong> Nature Genet. 12: 195-199, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8563760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8563760</a>] [<a href="https://doi.org/10.1038/ng0296-195" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8563760">Lindberg et al. (1996)</a> generated Pbgd-deficient mice by gene targeting. These mice exhibited typical biochemical characteristics of human AIP, including decreased hepatic Pbgd activity, increased delta-aminolevulinic acid synthase (ALAS1; <a href="/entry/125290">125290</a>) activity, and massively increased urinary excretion of the heme precursor delta-aminolevulinic acid after treatment with drugs such as phenobarbital. Behavioral tests revealed decreased motor function and histopathologic findings, including axonal neuropathy and neurologic muscle atrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8563760" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Homedan, C., Schmitt, C., Laafi, J., Gueguen, N., Desquiret-Dumas, V., Lenglet, H., Karim, Z., Gouya, L., Deybach, J.-C., Simard, G., Puy, H., Malthiery, Y., Reynier, P. <strong>Mitochondrial energy defects in muscle and brain of a Hmbs -/- mouse model of acute intermittent porphyria.</strong> Hum. Molec. Genet. 24: 5015-5023, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26071363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26071363</a>] [<a href="https://doi.org/10.1093/hmg/ddv222" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26071363">Homedan et al. (2015)</a> studied the AIP mouse model generated by <a href="#29" class="mim-tip-reference" title="Lindberg, R. L. P., Porcher, C., Grandchamp, B., Ledermann, B., Burki, K., Brandner, S., Aguzzi, A., Meyer, U. A. <strong>Porphobilinogen deaminase deficiency in mice causes a neuropathy resembling that of human hepatic porphyria.</strong> Nature Genet. 12: 195-199, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8563760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8563760</a>] [<a href="https://doi.org/10.1038/ng0296-195" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8563760">Lindberg et al. (1996)</a>, in which the mice were compound heterozygous for a null Hmbs allele and a functional Hmbs allele with a mild mutation. They had previously found that Hmbs mutant liver showed deficiencies in mitochondrial complexes I through III. <a href="#22" class="mim-tip-reference" title="Homedan, C., Schmitt, C., Laafi, J., Gueguen, N., Desquiret-Dumas, V., Lenglet, H., Karim, Z., Gouya, L., Deybach, J.-C., Simard, G., Puy, H., Malthiery, Y., Reynier, P. <strong>Mitochondrial energy defects in muscle and brain of a Hmbs -/- mouse model of acute intermittent porphyria.</strong> Hum. Molec. Genet. 24: 5015-5023, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26071363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26071363</a>] [<a href="https://doi.org/10.1093/hmg/ddv222" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26071363">Homedan et al. (2015)</a> found tissue-specific alterations in mitochondrial complexes in Hmbs mutant brain and muscle in the basal state. Phenobarbital-induced AIP was accompanied by a sharp alteration of oxidative metabolism in muscle, with significantly decreased ATP production in Hmbs mutant skeletal muscle due to deficiencies in complexes I and II. In contrast, all 4 respiratory chain complexes were affected in Hmbs mutant brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8563760+26071363" 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="Clavero, S., Bishop, D. F., Haskins, M. E., Giger, U., Kauppinen, R., Desnick, R. J. <strong>Feline acute intermittent porphyria: a phenocopy masquerading as an erythropoietic porphyria due to dominant and recessive hydroxymethylbilane synthase mutations.</strong> Hum. Molec. Genet. 19: 584-596, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19934113/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19934113</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19934113[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/10.1093/hmg/ddp525" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19934113">Clavero et al. (2010)</a> described a naturally occurring feline model of AIP in 4 unrelated cat lines that presented phenotypically as congenital erythropoietic porphyria (CEP; <a href="/entry/263700">263700</a>). Affected cats had erythrodontia, brownish urine, fluorescent bones, and markedly elevated urinary uroporphyrin and coproporphyrin, consistent with CEP. However, their UROS activities (deficient in CEP) were normal. Notably, affected cats had half-normal HMBS activities and elevated urinary 5-aminolevulinic acid (5-ALA) and PBG. Sequencing the feline Hmbs gene revealed different mutations in each line, including a duplication, an in-frame 3-bp deletion (842delGAG), and 2 missense (A84T and R149W) mutations. The 842delGAG and R149W mutations were identical to mutations reported in human. Prokaryotic expression of the 842delGAG and R149W mutations resulted in mutant enzymes with less than 1% wildtype activity, whereas the A84T mutation expressed a stable enzyme with approximately 35% of wildtype activity. The discolored teeth from the affected cats contained markedly elevated URO I and III, accounting for the CEP-like phenocopy. In 3 lines, the phenotype was an autosomal dominant trait, while affected cats with the A84T mutation were homozygous, a unique recessive form of AIP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19934113" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#59" class="mim-tip-reference" title="Yasuda, M., Gan, L., Chen, B., Yu, C., Zhang, J., Gama-Sosa, M. A., Pollak, D. D., Berger, S., Phillips, J. D., Edelmann, W., Desnick, R. J. <strong>Homozygous hydroxymethylbilane synthase knock-in mice provide pathogenic insights into the severe neurological impairments present in human homozygous dominant acute intermittent porphyria.</strong> Hum. Molec. Genet. 28: 1755-1767, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30615115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30615115</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30615115[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/10.1093/hmg/ddz003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30615115">Yasuda et al. (2019)</a> developed 2 separate mouse models with compound heterozygous missense mutations in the Hmbs gene: R167Q (<a href="#0005">609806.0005</a>) and R173Q (<a href="#0006">609806.0006</a>). Homozygosity for the R173Q mutation resulted in 1% of normal Hmbs activity and was embryonic lethal, whereas homozygosity for the R167Q mutation resulted in approximately 5% of normal Hmbs activity. Homozygous R167Q mice had elevated plasma and urinary 5-ALA and PBG at baseline, thought to be due to local production rather than transport through the blood brain barrier, and phenotypic features of delayed eye opening, severe early-onset ataxia, delayed motor development, and abnormal rotarod performance at 2 to 3 months of age, which progressively worsened. Brain myelination was delayed and total myelin volume was decreased by approximately 30% compared to wildtype littermates. In comparison to the T1/T2 mouse model of AIP, which has approximately 30% residual Hmbs activity, heme concentrations in liver and brain were similar, whereas 5-ALA and PBG concentrations were elevated in brain and CSF in R167Q mice. This suggests that the 5-ALA and PBG underlie the neurologic phenotype as opposed to reduced heme. Porphyrinogenic stimuli, including fasting and phenobarbital administration, led to no or mild changes in Alas1 mRNA levels and 5-ALA and PBG levels. R167Q homozygous mice had grossly normal brain and spinal cord at age 12 months and normal femoral nerve structures at age 6 months. (In the article by <a href="#59" class="mim-tip-reference" title="Yasuda, M., Gan, L., Chen, B., Yu, C., Zhang, J., Gama-Sosa, M. A., Pollak, D. D., Berger, S., Phillips, J. D., Edelmann, W., Desnick, R. J. <strong>Homozygous hydroxymethylbilane synthase knock-in mice provide pathogenic insights into the severe neurological impairments present in human homozygous dominant acute intermittent porphyria.</strong> Hum. Molec. Genet. 28: 1755-1767, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30615115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30615115</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30615115[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/10.1093/hmg/ddz003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30615115">Yasuda et al. (2019)</a>, the mutations were also stated as Arg167Glu and Arg173Glu, which would be R167E and R173E, respectively. <a href="#60" class="mim-tip-reference" title="Yasuda, M. <strong>Personal Communication.</strong> New York, N.Y. 10/21/2020."None>Yasuda (2020)</a> confirmed that the mutations are Arg167Gln (R167Q) and Arg173Gln (R173Q).) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30615115" 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="Berger, S., Stattmann, M., Cicvaric, A., Monje, F. J., Coiro, P., Hotka, M., Ricken, G., Hainfellner, J., Greber-Platzer, S., Yasuda, M., Desnick, R. J., Pollak, D. D. <strong>Severe hydroxymethylbilane synthase deficiency causes depression-like behavior and mitochondrial dysfunction in a mouse model of homozygous dominant acute intermittent porphyria.</strong> Acta Neuropath. Commun. 8: 38, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32197664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32197664</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32197664[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/10.1186/s40478-020-00910-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32197664">Berger et al. (2020)</a> found that mice homozygous for the R167Q mutation in the Hmbs gene (<a href="#0005">609806.0005</a>) showed depression-like behavioral abnormalities. RNA-seq analysis of hippocampal tissue from mutant mice showed differentially expressed genes (DEGs) compared to controls. The DEGs were involved in myelination in the CNS and oligodendrocyte development. Mutant mice had fewer hippocampal oligodendrocytes compared to controls and there was evidence of disrupted mitochondrial energy metabolism. Hippocampal neurons in mutant mice showed impaired neuronal cell proliferation and differentiation and aberrant synaptic plasticity. The findings implicated defective myelination as the pathogenic mechanism in the behavioral and neuronal plasticity defects and suggested that mitochondrial dysfunction may play a role. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32197664" 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">rs1565750784 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1565750784;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=rs1565750784" 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=rs1565750784" 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=RCV000001506 OR RCV002512650" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001506, RCV002512650" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001506...</a>
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<p>In affected members of a large Dutch family with the nonerythroid variant of acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#16" class="mim-tip-reference" title="Grandchamp, B., Picat, C., Mignotte, V., Wilson, J. H. P., te Velde, K., Sandkuyl, L., Romeo, P. H., Goossens, M., Nordmann, Y. <strong>Tissue-specific splicing mutation in acute intermittent porphyria.</strong> Proc. Nat. Acad. Sci. 86: 661-664, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2563167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2563167</a>] [<a href="https://doi.org/10.1073/pnas.86.2.661" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2563167">Grandchamp et al. (1989)</a> identified a heterozygous G-to-A transition in the 5-prime splice donor site of intron 1 of the HMBS gene. The mutation interrupted the sequence coding for the nonerythroid isoform of PBGD; thus, expression of the erythroid isoform was unaffected. Hybridization analysis using oligonucleotide probes after in vitro amplification of genomic DNA offered another possibility of detecting asymptomatic carriers of the mutation in affected families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2563167" 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>Puy et al. (<a href="#47" class="mim-tip-reference" title="Puy, H., Deybach, J. C., Lamoril, J., Robreau, A. M., Da Silva, V., Gouya, L., Grandchamp, B., Nordmann, Y. <strong>Molecular epidemiology and diagnosis of PBG deaminase gene defects in acute intermittent porphyria.</strong> Am. J. Hum. Genet. 60: 1373-1383, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9199558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9199558</a>] [<a href="https://doi.org/10.1086/515455" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9199558">1997</a>, <a href="#48" class="mim-tip-reference" title="Puy, H., Gross, U., Deybach, J. C., Robreau, A. M., Frank, M., Nordmann, Y., Doss, M. <strong>Exon 1 donor splice site mutations in the porphobilinogen deaminase gene in the non-erythroid variant form of acute intermittent porphyria.</strong> Hum. Genet. 103: 570-575, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9860299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9860299</a>] [<a href="https://doi.org/10.1007/s004390050871" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9860299">1998</a>) identified this splice site mutation in patients with nonerythroid variant AIP. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9199558+9860299" 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="#44" class="mim-tip-reference" title="Petrides, P. E. <strong>Acute intermittent porphyria: mutation analysis and identification of gene carriers in a German kindred by PCR-DGGE analysis.</strong> Skin Pharmacol. Appl. Skin Physiol. 11: 374-380, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10343207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10343207</a>] [<a href="https://doi.org/10.1159/000029859" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10343207">Petrides (1998)</a> identified the G-to-A transition in intron 1 of the HMBS gene in 9 members of a German kindred in which the proband had a life-threatening coma due to the nonerythroid variant of AIP. The newly identified family members were taught how to prevent porphyric attacks. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10343207" 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">rs1555206170 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555206170;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=rs1555206170" 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=rs1555206170" 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=RCV000578508 OR RCV002255098" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000578508, RCV002255098" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000578508...</a>
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<p>In a patient with acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#14" class="mim-tip-reference" title="Grandchamp, B., Picat, C., de Rooij, F., Beaumont, C., Wilson, P., Deybach, J. C., Nordmann, Y. <strong>A point mutation G-to-A in exon 12 of the porphobilinogen deaminase gene results in exon skipping and is responsible for acute intermittent porphyria.</strong> Nucleic Acids Res. 17: 6637-6649, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2789372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2789372</a>] [<a href="https://doi.org/10.1093/nar/17.16.6637" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2789372">Grandchamp et al. (1989)</a> identified a heterozygous G-to-A transition in exon 12 of the HMBS gene, resulting in the skipping of exon 12. The resulting aberrant mRNA encoded a truncated protein that was inactive, but stable, and could be detected using antibodies directed against the normal enzyme (CRM-positive). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2789372" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 PORPHYRIA, ACUTE INTERMITTENT, NONERYTHROID VARIANT</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">rs1565750784 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1565750784;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=rs1565750784" 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=rs1565750784" 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=RCV000001509 OR RCV002512651" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001509, RCV002512651" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001509...</a>
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<p>In a Finnish family with the nonerythroid variant of acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>) <a href="#15" class="mim-tip-reference" title="Grandchamp, B., Picat, C., Kauppinen, R., Mignotte, V., Peltonen, L., Mustajoki, P., Romeo, P. H., Goossens, M., Nordmann, Y. <strong>Molecular analysis of acute intermittent porphyria in a Finnish family with normal erythrocyte porphobilinogen deaminase.</strong> Europ. J. Clin. Invest. 19: 415-418, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2511016/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2511016</a>] [<a href="https://doi.org/10.1111/j.1365-2362.1989.tb00252.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2511016">Grandchamp et al. (1989)</a> identified a G-to-T transversion in the 5-prime splice donor sequence of intron 1 of the HMBS gene. This is only 1 nucleotide removed from the mutation listed as <a href="#0001">609806.0001</a>, in which the change occurred in the first nucleotide of intron 1. <a href="#15" class="mim-tip-reference" title="Grandchamp, B., Picat, C., Kauppinen, R., Mignotte, V., Peltonen, L., Mustajoki, P., Romeo, P. H., Goossens, M., Nordmann, Y. <strong>Molecular analysis of acute intermittent porphyria in a Finnish family with normal erythrocyte porphobilinogen deaminase.</strong> Europ. J. Clin. Invest. 19: 415-418, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2511016/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2511016</a>] [<a href="https://doi.org/10.1111/j.1365-2362.1989.tb00252.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2511016">Grandchamp et al. (1989)</a> proposed that both of these mutations resulted in an abnormal splicing of primary transcripts initiated at the upstream promoter of the gene without affecting the expression of the PBGD gene in erythroid cells where the downstream promoter is utilized. A similar mutation located at the last position of exon 1 of the beta-globin gene was found by <a href="#55" class="mim-tip-reference" title="Vidaud, M., Gattoni, R., Stevenin, J., Vidaud, D., Amselem, S., Chibani, J., Rosa, J., Goossens, M. <strong>A 5-prime splice-region G-to-C mutation in exon 1 of the human beta-globin gene inhibits pre-mRNA splicing: a mechanism for beta(+)-thalassemia.</strong> Proc. Nat. Acad. Sci. 86: 1041-1045, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2915972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2915972</a>] [<a href="https://doi.org/10.1073/pnas.86.3.1041" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2915972">Vidaud et al. (1989)</a> to be responsible for a splicing defect leading to beta-thalassemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2511016+2915972" 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> rs118204094 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204094;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/rs118204094?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=rs118204094" 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=rs118204094" 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=RCV000001510 OR RCV001212053" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001510, RCV001212053" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001510...</a>
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<p>In affected members of a Swedish family with acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#28" class="mim-tip-reference" title="Lee, J.-S., Grandchamp, B., Anvret, M. <strong>A point mutation of the human porphobilinogen deaminase gene in a Swedish family with acute intermittent porphyria. (Abstract)</strong> Am. J. Hum. Genet. 47 (suppl.): A162, 1990."None>Lee et al. (1990)</a> identified a C-to-T transition in exon 8 of the HMBS gene, resulting in an arg116-to-trp (R116W) substitution.</p><p>The R116W mutation was found by <a href="#17" class="mim-tip-reference" title="Gu, X.-F., de Rooij, F., Lee, J. S., te Velde, K., Deybach, J.-C., Nordmann, Y., Grandchamp, B. <strong>High prevalence of a point mutation in the porphobilinogen deaminase gene in Dutch patients with acute intermittent porphyria.</strong> Hum. Genet. 91: 128-130, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8096492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8096492</a>] [<a href="https://doi.org/10.1007/BF00222712" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8096492">Gu et al. (1993)</a> in 15 Dutch AIP families and in 1 French AIP family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8096492" 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> rs118204095 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204095;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/rs118204095?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=rs118204095" 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=rs118204095" 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=RCV000001511 OR RCV000520560 OR RCV003764509 OR RCV003764510" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001511, RCV000520560, RCV003764509, RCV003764510" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001511...</a>
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<p><strong><em>Acute Intermittent Porphyria</em></strong></p><p>
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In patients with acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#10" class="mim-tip-reference" title="Delfau, M. H., Picat, C., de Rooij, F. W. M., Hamer, K., Bogard, M., Wilson, J. H. P., Deybach, J. C., Nordmann, Y., Grandchamp, B. <strong>Two different point G to A mutations in exon 10 of the porphobilinogen deaminase gene are responsible for acute intermittent porphyria.</strong> J. Clin. Invest. 86: 1511-1516, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2243128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2243128</a>] [<a href="https://doi.org/10.1172/JCI114869" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2243128">Delfau et al. (1990)</a> identified a heterozygous G-to-A transition in exon 10 of the HMBS gene, resulting in an arg167-to-gln (R167Q) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2243128" 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>Porphyria-Related Encephalopathy</em></strong></p><p>
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In a Dutch girl with porphyria-related encephalopathy (ENCEP; <a href="/entry/620704">620704</a>) originally reported by <a href="#2" class="mim-tip-reference" title="Beukeveld, G. J. J., Wolthers, B. G., Nordmann, Y., Deybach, J. C., Grandchamp, B., Wadman, S. K. <strong>A retrospective study of a patient with homozygous form of acute intermittent porphyria.</strong> J. Inherit. Metab. Dis. 13: 673-683, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2246851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2246851</a>] [<a href="https://doi.org/10.1007/BF01799566" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2246851">Beukeveld et al. (1990)</a>, <a href="#45" class="mim-tip-reference" title="Picat, C., Delfau, M. H., de Rooij, F. W. M., Beukeveld, G. J. J., Wolthers, B. G., Wadman, S. K., Nordmann, Y., Grandchamp, B. <strong>Identification of the mutations in the parents of a patient with a putative compound heterozygosity for acute intermittent porphyria.</strong> J. Inherit. Metab. Dis. 13: 684-686, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2246852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2246852</a>] [<a href="https://doi.org/10.1007/BF01799567" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2246852">Picat et al. (1990)</a> identified compound heterozygous missense mutations in the HMBS gene: R167Q and R173Q (<a href="#0006">609806.0006</a>). The parents, who had classic AIP, were each heterozygous for 1 of the mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2246851+2246852" 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 an English brother and sister with ENCEP, <a href="#31" class="mim-tip-reference" title="Llewellyn, D. H., Smyth, S. J., Elder, G. H., Hutchesson, A. C., Rattenbury, J. M., Smith, M. F. <strong>Homozygous acute intermittent porphyria: compound heterozygosity for adjacent base transitions in the same codon of the porphobilinogen deaminase gene.</strong> Hum. Genet. 89: 97-98, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1577472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1577472</a>] [<a href="https://doi.org/10.1007/BF00207051" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1577472">Llewellyn et al. (1992)</a> identified compound heterozygosity for 2 mutations in the HMBS gene: a c.500G-A transition, resulting in an R167Q substitution, and a c.499C-T transition, resulting in an R167W substitution (<a href="#0013">609806.0013</a>). Erythrocyte HMBS activity ranged from 14 to 17% of controls. Each clinically unaffected parent was heterozygous for 1 of the variants and had about a 50% reduction in HMBS activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1577472" 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>Porphyria-Related Leukoencephalopathy</em></strong></p><p>
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For discussion of the R167Q mutation (c.500G-A, NM_000190.3) in the HMBS gene that was found in compound heterozygous state with R225Q (<a href="#0047">609806.0047</a>) in 2 Dutch families with porphyria-related leukoencephalopathy (LENCEP; <a href="/entry/620711">620711</a>) by <a href="#25" class="mim-tip-reference" title="Kevelam, S. H., Neeleman, R. A., Waisfisz, Q., Friesema, E. C. H., Langendonk, J. G., van der Knaap, M. S. <strong>Acute intermittent porphyria-related leukoencephalopathy.</strong> Neurology 87: 1258-1265, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27558376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27558376</a>] [<a href="https://doi.org/10.1212/WNL.0000000000003129" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27558376">Kevelam et al. (2016)</a> and <a href="#53" class="mim-tip-reference" title="Stutterd, C. A., Kidd, A., Florkowski, C., Janus, E., Fanjul, M., Raizis, A., Wu, T. Y., Archer, J., Leventer, R. J., Amor, D. J., Lukic, V., Bahlo, M., Gow, P., Lockhart, P. J., van der Knaap, M. S., Delatycki, M. B. <strong>Expanding the clinical and radiological phenotypes of leukoencephalopathy due to biallelic HMBS mutations.</strong> Am. J. Med. Genet. 185A: 2941-2950, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34089223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34089223</a>] [<a href="https://doi.org/10.1002/ajmg.a.62377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34089223">Stutterd et al. (2021)</a>, see <a href="#0047">609806.0047</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=34089223+27558376" 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>Variant Function</em></strong></p><p>
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In in vitro studies, <a href="#52" class="mim-tip-reference" title="Solis, C., Martinez-Bermejo, A., Naidich, T. P., Kaufmann, W. E., Astrin, K. H., Bishop, D. F., Desnick, R. J. <strong>Acute intermittent porphyria: studies of the severe homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias.</strong> Arch. Neurol. 61: 1764-1770, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15534187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15534187</a>] [<a href="https://doi.org/10.1001/archneur.61.11.1764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15534187">Solis et al. (2004)</a> found that the R167Q variant had about 1% residual HMBS activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15534187" 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">rs118204096 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204096;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=rs118204096" 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=rs118204096" 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=RCV000001512 OR RCV001851550 OR RCV003764511" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001512, RCV001851550, RCV003764511" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001512...</a>
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<p><strong><em>Acute Intermittent Porphyria</em></strong></p><p>
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In patients with acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#10" class="mim-tip-reference" title="Delfau, M. H., Picat, C., de Rooij, F. W. M., Hamer, K., Bogard, M., Wilson, J. H. P., Deybach, J. C., Nordmann, Y., Grandchamp, B. <strong>Two different point G to A mutations in exon 10 of the porphobilinogen deaminase gene are responsible for acute intermittent porphyria.</strong> J. Clin. Invest. 86: 1511-1516, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2243128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2243128</a>] [<a href="https://doi.org/10.1172/JCI114869" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2243128">Delfau et al. (1990)</a> identified a heterozygous G-to-A transition in exon 10 of the HMBS gene, resulting in an arg173-to-gln (R173Q) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2243128" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Kauppinen, R., Peltonen, L., Pihlaja, H., Mustajoki, P. <strong>CRIM-positive mutations of acute intermittent porphyria in Finland.</strong> Hum. Mutat. 1: 392-396, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301948</a>] [<a href="https://doi.org/10.1002/humu.1380010508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1301948">Kauppinen et al. (1992)</a> identified the R173Q substitution in 3 out of 7 Finnish families with CRM-positive AIP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1301948" 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>Porphyria-Related Encephalopathy</em></strong></p><p>
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In a Dutch patient with porphyria-related encephalopathy (ENCEP; <a href="/entry/620704">620704</a>) originally reported by <a href="#2" class="mim-tip-reference" title="Beukeveld, G. J. J., Wolthers, B. G., Nordmann, Y., Deybach, J. C., Grandchamp, B., Wadman, S. K. <strong>A retrospective study of a patient with homozygous form of acute intermittent porphyria.</strong> J. Inherit. Metab. Dis. 13: 673-683, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2246851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2246851</a>] [<a href="https://doi.org/10.1007/BF01799566" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2246851">Beukeveld et al. (1990)</a>, <a href="#45" class="mim-tip-reference" title="Picat, C., Delfau, M. H., de Rooij, F. W. M., Beukeveld, G. J. J., Wolthers, B. G., Wadman, S. K., Nordmann, Y., Grandchamp, B. <strong>Identification of the mutations in the parents of a patient with a putative compound heterozygosity for acute intermittent porphyria.</strong> J. Inherit. Metab. Dis. 13: 684-686, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2246852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2246852</a>] [<a href="https://doi.org/10.1007/BF01799567" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2246852">Picat et al. (1990)</a> identified compound heterozygous missense mutations in the HMBS gene: R173Q and R167Q (<a href="#0005">609806.0005</a>). The parents, who had symptomatic AIP (the mother) or latent AIP (the father), were each heterozygous for 1 of the mutations and had about 50% decreased erythrocyte HMBS activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2246851+2246852" 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="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000001513" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001513" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001513</a>
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<p>In 1 of 43 unrelated patients with acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#51" class="mim-tip-reference" title="Scobie, G. A., Llewellyn, D. H., Urquhart, A. J., Smyth, S. J., Kalsheker, N. A., Harrison, P. R., Elder, G. H. <strong>Acute intermittent porphyria caused by a C-to-T mutation that produces a stop codon in the porphobilinogen deaminase gene.</strong> Hum. Genet. 85: 631-634, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2227955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2227955</a>] [<a href="https://doi.org/10.1007/BF00193588" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2227955">Scobie et al. (1990)</a> identified a C-to-T transition in the HMBS gene, resulting in a gln155-to-ter (Q155X) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2227955" 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">rs118204098 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204098;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=rs118204098" 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=rs118204098" 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 patient with acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#9" class="mim-tip-reference" title="Delfau, M. H., Picat, C., De Rooij, F., Voortman, G., Deybach, J. C., Nordmann, Y., Grandchamp, B. <strong>Molecular heterogeneity of acute intermittent porphyria: identification of four additional mutations resulting in the CRIM-negative subtype of the disease.</strong> Am. J. Hum. Genet. 49: 421-428, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1714233/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1714233</a>]" pmid="1714233">Delfau et al. (1991)</a> identified a c.446G-A transition in exon 9 of the HMBS gene, resulting in an arg149-to-gln (R159Q) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1714233" 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="0009" class="mim-anchor"></a>
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<strong>.0009 PORPHYRIA, ACUTE INTERMITTENT</strong>
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HMBS, LEU245ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs118204099 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204099;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=rs118204099" 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=rs118204099" 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=RCV000001515" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001515" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001515</a>
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<p>In a patient with acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#9" class="mim-tip-reference" title="Delfau, M. H., Picat, C., De Rooij, F., Voortman, G., Deybach, J. C., Nordmann, Y., Grandchamp, B. <strong>Molecular heterogeneity of acute intermittent porphyria: identification of four additional mutations resulting in the CRIM-negative subtype of the disease.</strong> Am. J. Hum. Genet. 49: 421-428, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1714233/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1714233</a>]" pmid="1714233">Delfau et al. (1991)</a> identified a c.734T-G transversion in exon 12 of the HMBS gene, resulting in a leu245-to-arg (L245R) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1714233" 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="0010" class="mim-anchor"></a>
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<strong>.0010 PORPHYRIA, ACUTE INTERMITTENT</strong>
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HMBS, 1-BP DEL, 900T
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1565758825 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1565758825;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=rs1565758825" 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=rs1565758825" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000001516" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001516" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001516</a>
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<p>In a patient with CRM-positive acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#9" class="mim-tip-reference" title="Delfau, M. H., Picat, C., De Rooij, F., Voortman, G., Deybach, J. C., Nordmann, Y., Grandchamp, B. <strong>Molecular heterogeneity of acute intermittent porphyria: identification of four additional mutations resulting in the CRIM-negative subtype of the disease.</strong> Am. J. Hum. Genet. 49: 421-428, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1714233/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1714233</a>]" pmid="1714233">Delfau et al. (1991)</a> identified a 1-bp deletion (c.900delT) in exon 1 of the HMBS gene, resulting in a stop codon located 15 codons downstream from the deletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1714233" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0011" class="mim-anchor"></a>
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<h4>
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<strong>.0011 PORPHYRIA, ACUTE INTERMITTENT</strong>
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HMBS, 9-BP DEL, EX10
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1592217847 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1592217847;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=rs1592217847" 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=rs1592217847" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000807846 OR RCV002249519" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000807846, RCV002249519" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000807846...</a>
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</span>
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<span class="mim-text-font">
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<p>In a patient with CRM-positive acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#9" class="mim-tip-reference" title="Delfau, M. H., Picat, C., De Rooij, F., Voortman, G., Deybach, J. C., Nordmann, Y., Grandchamp, B. <strong>Molecular heterogeneity of acute intermittent porphyria: identification of four additional mutations resulting in the CRIM-negative subtype of the disease.</strong> Am. J. Hum. Genet. 49: 421-428, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1714233/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1714233</a>]" pmid="1714233">Delfau et al. (1991)</a> identified a deletion of the last 9 bp of exon 10. This resulted from abnormal splicing of intron 10 which was a consequence of a G-to-T substitution of the last base of exon 10. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1714233" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0012" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0012 PORPHYRIA, ACUTE INTERMITTENT</strong>
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HMBS, TRP198TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs118204100 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204100;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=rs118204100" 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=rs118204100" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000001518" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001518" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001518</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a northern Swedish (Lappland) family with acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#27" class="mim-tip-reference" title="Lee, J.-S., Anvret, M. <strong>Identification of the most common mutation within the porphobilinogen deaminase gene in Swedish patients with acute intermittent porphyria.</strong> Proc. Nat. Acad. Sci. 88: 10912-10915, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1961762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1961762</a>] [<a href="https://doi.org/10.1073/pnas.88.23.10912" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1961762">Lee and Anvret (1991)</a> identified a G-to-A transition in exon 10 of the HMBS gene, resulting in a trp198-to-ter (W198X) substitution. The same mutation was found in 15 of 33 Swedish AIP families. Genealogic data showed that 12 of the 15 were related, indicating a founder effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1961762" 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="0013" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0013 PORPHYRIA, ACUTE INTERMITTENT</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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ENCEPHALOPATHY, PORPHYRIA-RELATED, INCLUDED
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HMBS, ARG167TRP
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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> rs118204101 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204101;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/rs118204101?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=rs118204101" 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=rs118204101" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000001521 OR RCV000489906 OR RCV003764512" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001521, RCV000489906, RCV003764512" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001521...</a>
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</span>
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<span class="mim-text-font">
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<p />
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<p><strong><em>Acute Intermittent Porphyria</em></strong></p><p>
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The seemingly high frequency of mutations in exon 10 of the PBGD gene (<a href="#10" class="mim-tip-reference" title="Delfau, M. H., Picat, C., de Rooij, F. W. M., Hamer, K., Bogard, M., Wilson, J. H. P., Deybach, J. C., Nordmann, Y., Grandchamp, B. <strong>Two different point G to A mutations in exon 10 of the porphobilinogen deaminase gene are responsible for acute intermittent porphyria.</strong> J. Clin. Invest. 86: 1511-1516, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2243128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2243128</a>] [<a href="https://doi.org/10.1172/JCI114869" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2243128">Delfau et al., 1990</a>) prompted <a href="#19" class="mim-tip-reference" title="Gu, X.-F., de Rooij, F., Voortman, G., te Velde, K., Nordmann, Y., Grandchamp, B. <strong>High frequency of mutations in exon 10 of the porphobilinogen deaminase gene in patients with a CRIM-positive subtype of acute intermittent porphyria.</strong> Am. J. Hum. Genet. 51: 660-665, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1496994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1496994</a>]" pmid="1496994">Gu et al. (1992)</a> to screen this exon in 41 unrelated patients with autosomal dominant AIP (AIP; <a href="/entry/176000">176000</a>) by use of denaturing gradient gel electrophoresis (DGGE) after PCR amplification. In about one-fourth of the patients, they distinguished 3 abnormal migration patterns, indicating the presence of mutation in heterozygous state. Sequencing demonstrated the presence of 3 different single-base substitutions: R167Q (<a href="#0005">609806.0005</a>), R173Q (<a href="#0006">609806.0006</a>), and R167W. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1496994+2243128" 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 Finland, <a href="#24" class="mim-tip-reference" title="Kauppinen, R., Peltonen, L., Pihlaja, H., Mustajoki, P. <strong>CRIM-positive mutations of acute intermittent porphyria in Finland.</strong> Hum. Mutat. 1: 392-396, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301948</a>] [<a href="https://doi.org/10.1002/humu.1380010508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1301948">Kauppinen et al. (1992)</a> found an R167W mutation in 3 out of 7 families with CRM-positive AIP. DNA analyses of family members demonstrated that conventional assays of erythrocyte PBGD activity identified correctly only 72% of the carriers of the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1301948" 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>Porphyria-Related Encephalopathy</em></strong></p><p>
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In an English brother and sister with porphyria-related encephalopathy (ENCEP; <a href="/entry/620704">620704</a>), <a href="#31" class="mim-tip-reference" title="Llewellyn, D. H., Smyth, S. J., Elder, G. H., Hutchesson, A. C., Rattenbury, J. M., Smith, M. F. <strong>Homozygous acute intermittent porphyria: compound heterozygosity for adjacent base transitions in the same codon of the porphobilinogen deaminase gene.</strong> Hum. Genet. 89: 97-98, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1577472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1577472</a>] [<a href="https://doi.org/10.1007/BF00207051" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1577472">Llewellyn et al. (1992)</a> identified compound heterozygosity for 2 mutations in the PBGD gene: a c.499C-T transition, resulting in an arg167-to-trp (R167W) substitution, and an adjacent c.500G-A transition, resulting in an R167Q (<a href="#0005">609806.0005</a>) substitution. Erythrocyte HMBS activity was 14 to 17% of normal controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1577472" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#52" class="mim-tip-reference" title="Solis, C., Martinez-Bermejo, A., Naidich, T. P., Kaufmann, W. E., Astrin, K. H., Bishop, D. F., Desnick, R. J. <strong>Acute intermittent porphyria: studies of the severe homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias.</strong> Arch. Neurol. 61: 1764-1770, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15534187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15534187</a>] [<a href="https://doi.org/10.1001/archneur.61.11.1764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15534187">Solis et al. (2004)</a> reported a Spanish patient with ENCEP who was homozygous for the R167W substitution. Both parents were heterozygous for the mutation. The patient had 1% residual HMBS activity. The clinically asymptomatic parents were heterozygous for the mutation and had about 50% HMBS activity. The proband had a severe disease course with psychomotor delay, dystonic movements, axial hypotonia, delayed myelination, and death at age 40 months. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15534187" 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>Variant Function</em></strong></p><p>
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<a href="#52" class="mim-tip-reference" title="Solis, C., Martinez-Bermejo, A., Naidich, T. P., Kaufmann, W. E., Astrin, K. H., Bishop, D. F., Desnick, R. J. <strong>Acute intermittent porphyria: studies of the severe homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias.</strong> Arch. Neurol. 61: 1764-1770, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15534187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15534187</a>] [<a href="https://doi.org/10.1001/archneur.61.11.1764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15534187">Solis et al. (2004)</a> noted that the R167W, R173Q, and R167Q mutations all occur at CpG dinucleotides within exon 10, and can thus be considered mutation hotspots. All 3 substitutions alter highly conserved arginines in the enzyme's active site, which interact with the precursor porphobilinogen and the acidic side chains of the enzyme's dipyrromethane cofactor. Functional expression studies showed that all 3 substitutions resulted in less than 2% normal HMBS activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15534187" 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 PORPHYRIA, ACUTE INTERMITTENT</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> rs118204095 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204095;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/rs118204095?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=rs118204095" 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=rs118204095" 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=RCV000001522" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001522" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001522</a>
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<p>Using site-directed mutagenesis, <a href="#26" class="mim-tip-reference" title="Lander, M., Pitt, A. R., Alefounder, P. R., Bardy, D., Abell, C., Battersby, A. R. <strong>Studies on the mechanism of hydroxymethyl bilane synthase concerning the role of arginine residues in substrate binding.</strong> Biochem. J. 275: 447-452, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2025226/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2025226</a>] [<a href="https://doi.org/10.1042/bj2750447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2025226">Lander et al. (1991)</a> demonstrated that an arg167-to-leu (R167L) substitution in the HMBS protein resulted in a profound decrease of PBGD activity, consistent with acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>). It is noteworthy that substitution of arg167 by glutamine (R167Q; <a href="#0005">609806.0005</a>) and by tryptophan (R167W; <a href="#0013">609806.0013</a>) resulted in loss of enzyme activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2025226" 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">rs118204103 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204103;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=rs118204103" 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=rs118204103" 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=RCV000001508 OR RCV000798844" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001508, RCV000798844" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001508...</a>
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<p>In a patient with CRM-positive acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#32" class="mim-tip-reference" title="Llewellyn, D. H., Whatley, S., Elder, G. H. <strong>Acute intermittent porphyria caused by an arginine to histidine substitution (R26H) in the cofactor-binding cleft of porphobilinogen deaminase.</strong> Hum. Molec. Genet. 2: 1315-1316, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8401516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8401516</a>] [<a href="https://doi.org/10.1093/hmg/2.8.1315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8401516">Llewellyn et al. (1993)</a> identified a c.77G-A transition in exon 3 of the HMBS gene, resulting in an arg26-to-his (R26H) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8401516" 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">rs118204104 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204104;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=rs118204104" 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=rs118204104" 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=RCV000001519" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001519" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001519</a>
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<p>In a patient with CRM-positive acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#18" class="mim-tip-reference" title="Gu, X.-F., de Rooij, F., Voortman, G., te Velde, K., Deybach, J. C., Nordmann, Y., Grandchamp, B. <strong>Detection of eleven mutations causing acute intermittent porphyria using denaturing gradient gel electrophoresis.</strong> Hum. Genet. 93: 47-52, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8270254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8270254</a>] [<a href="https://doi.org/10.1007/BF00218912" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8270254">Gu et al. (1994)</a> identified a c.91G-A transition in exon 4 of the HMBS gene, leading to an ala31-to-thr (A31T) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8270254" 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">rs118204105 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204105;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=rs118204105" 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=rs118204105" 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=RCV000001520" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001520" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001520</a>
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<p>In a patient with CRM-negative acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#40" class="mim-tip-reference" title="Mgone, C. S., Lanyon, W. G., Moore, M. R., Connor, J. M. <strong>Detection of seven point mutations in the porphobilinogen deaminase gene in patients with acute intermittent porphyria, by direct sequencing of in vitro amplified cDNA.</strong> Hum. Genet. 90: 12-16, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1427766/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1427766</a>] [<a href="https://doi.org/10.1007/BF00210738" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1427766">Mgone et al. (1992)</a> identified a c.100C-A transversion in exon 4 of the HMBS gene, resulting in a gln34-to-lys (Q34K) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1427766" 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>.0018 PORPHYRIA, ACUTE INTERMITTENT</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">rs118204106 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204106;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=rs118204106" 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=rs118204106" 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=RCV000001523 OR RCV002272005 OR RCV003234886" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001523, RCV002272005, RCV003234886" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001523...</a>
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<p>In a patient with CRM-positive acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#18" class="mim-tip-reference" title="Gu, X.-F., de Rooij, F., Voortman, G., te Velde, K., Deybach, J. C., Nordmann, Y., Grandchamp, B. <strong>Detection of eleven mutations causing acute intermittent porphyria using denaturing gradient gel electrophoresis.</strong> Hum. Genet. 93: 47-52, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8270254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8270254</a>] [<a href="https://doi.org/10.1007/BF00218912" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8270254">Gu et al. (1994)</a> identified a c.163G-T transversion in exon 5 of the HMBS gene, resulting in an ala55-to-ser (A55S) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8270254" 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>.0019 PORPHYRIA, ACUTE INTERMITTENT</strong>
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HMBS, 1-BP DEL, 174C
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1565754285 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1565754285;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=rs1565754285" 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=rs1565754285" 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=RCV000001524" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001524" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001524</a>
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<p>In a patient with CRM-negative acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#18" class="mim-tip-reference" title="Gu, X.-F., de Rooij, F., Voortman, G., te Velde, K., Deybach, J. C., Nordmann, Y., Grandchamp, B. <strong>Detection of eleven mutations causing acute intermittent porphyria using denaturing gradient gel electrophoresis.</strong> Hum. Genet. 93: 47-52, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8270254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8270254</a>] [<a href="https://doi.org/10.1007/BF00218912" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8270254">Gu et al. (1994)</a> identified a 1-bp deletion (c.174delC) in exon 5 of the HMBS gene. This frameshift mutation leads to a premature termination 40 codons downstream and a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8270254" 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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<h4>
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<span class="mim-font">
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<strong>.0020 PORPHYRIA, ACUTE INTERMITTENT</strong>
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HMBS, 1-BP INS, 182G
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1565754296 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1565754296;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=rs1565754296" 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=rs1565754296" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000001525" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001525" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001525</a>
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<span class="mim-text-font">
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<p>In a patient with CRM-negative acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#18" class="mim-tip-reference" title="Gu, X.-F., de Rooij, F., Voortman, G., te Velde, K., Deybach, J. C., Nordmann, Y., Grandchamp, B. <strong>Detection of eleven mutations causing acute intermittent porphyria using denaturing gradient gel electrophoresis.</strong> Hum. Genet. 93: 47-52, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8270254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8270254</a>] [<a href="https://doi.org/10.1007/BF00218912" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8270254">Gu et al. (1994)</a> identified a 1-bp insertion (c.182insG) in exon 5 of the HMBS gene. This frameshift mutation leads to a premature termination 5 codons downstream and a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8270254" 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="0021" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0021 PORPHYRIA, ACUTE INTERMITTENT</strong>
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HMBS, IVS5DS, G-A, +1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1565754452 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1565754452;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=rs1565754452" 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=rs1565754452" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000001526" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001526" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001526</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with CRM-negative acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#18" class="mim-tip-reference" title="Gu, X.-F., de Rooij, F., Voortman, G., te Velde, K., Deybach, J. C., Nordmann, Y., Grandchamp, B. <strong>Detection of eleven mutations causing acute intermittent porphyria using denaturing gradient gel electrophoresis.</strong> Hum. Genet. 93: 47-52, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8270254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8270254</a>] [<a href="https://doi.org/10.1007/BF00218912" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8270254">Gu et al. (1994)</a> identified a c.210G-A substitution in the first nucleotide of the donor splice site of intron 5 of the HMBS gene, resulting in abnormal splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8270254" 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="0022" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0022 PORPHYRIA, ACUTE INTERMITTENT</strong>
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</h4>
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HMBS, 2-BP DEL, 218AG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1592214498 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1592214498;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=rs1592214498" 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=rs1592214498" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000809200 OR RCV002280823" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000809200, RCV002280823" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000809200...</a>
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</span>
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<span class="mim-text-font">
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<p>In a patient with CRM-negative acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#18" class="mim-tip-reference" title="Gu, X.-F., de Rooij, F., Voortman, G., te Velde, K., Deybach, J. C., Nordmann, Y., Grandchamp, B. <strong>Detection of eleven mutations causing acute intermittent porphyria using denaturing gradient gel electrophoresis.</strong> Hum. Genet. 93: 47-52, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8270254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8270254</a>] [<a href="https://doi.org/10.1007/BF00218912" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8270254">Gu et al. (1994)</a> identified a 2-bp deletion (c.218delAG) in exon 6 of the HMBS gene. This frameshift mutation leads to a premature termination 9 codons downstream and a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8270254" 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="0023" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0023 PORPHYRIA, ACUTE INTERMITTENT</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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HMBS, GLY111ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs118204107 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204107;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=rs118204107" 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=rs118204107" 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=RCV000001529 OR RCV001381874" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001529, RCV001381874" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001529...</a>
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<p>In a patient with CRM-negative acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#18" class="mim-tip-reference" title="Gu, X.-F., de Rooij, F., Voortman, G., te Velde, K., Deybach, J. C., Nordmann, Y., Grandchamp, B. <strong>Detection of eleven mutations causing acute intermittent porphyria using denaturing gradient gel electrophoresis.</strong> Hum. Genet. 93: 47-52, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8270254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8270254</a>] [<a href="https://doi.org/10.1007/BF00218912" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8270254">Gu et al. (1994)</a> identified a c.331G-A transition in exon 7 of the HMBS gene, resulting in a gly111-to-arg (G111R) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8270254" 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 Argentina, <a href="#7" class="mim-tip-reference" title="De Siervi, A., Rossetti, M. V., Parera, V. E., Astrin, K. H., Aizencang, G. I., Glass, I. A., Batlle, A. M. del C., Desnick, R. J. <strong>Identification and characterization of hydroxymethylbilane synthase mutations causing acute intermittent porphyria: evidence for an ancestral founder of the common G111R mutation.</strong> Am. J. Med. Genet. 86: 366-375, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10494093/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10494093</a>]" pmid="10494093">De Siervi et al. (1999)</a> found that the G111R mutation was present in 12 of 26 (46%) presumably unrelated propositi with AIP; haplotype analysis with intragenic and flanking markers indicated an ancestral founder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10494093" 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">rs1565756481 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1565756481;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=rs1565756481" 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=rs1565756481" 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=RCV000001530 OR RCV001389654" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001530, RCV001389654" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001530...</a>
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<p>In a patient with acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#35" class="mim-tip-reference" title="Lundin, G., Wedell, A., Thunell, S., Anvret, M. <strong>Two new mutations in the porphobilinogen deaminase gene and a screening method using PCR amplification of specific alleles.</strong> Hum. Genet. 93: 59-62, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8270256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8270256</a>] [<a href="https://doi.org/10.1007/BF00218914" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8270256">Lundin et al. (1994)</a> identified a c.499G-A transition in the first nucleotide of the acceptor splice site of intron 9 of the HMBS gene, resulting in abnormal splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8270256" 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>.0025 PORPHYRIA, ACUTE INTERMITTENT</strong>
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HMBS, LEU177ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs118204108 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204108;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=rs118204108" 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=rs118204108" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000001531 OR RCV000795368" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001531, RCV000795368" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001531...</a>
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<p>In affected members of several unrelated Finnish and Dutch families with acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#40" class="mim-tip-reference" title="Mgone, C. S., Lanyon, W. G., Moore, M. R., Connor, J. M. <strong>Detection of seven point mutations in the porphobilinogen deaminase gene in patients with acute intermittent porphyria, by direct sequencing of in vitro amplified cDNA.</strong> Hum. Genet. 90: 12-16, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1427766/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1427766</a>] [<a href="https://doi.org/10.1007/BF00210738" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1427766">Mgone et al. (1992)</a> identified a c.530T-G transversion in exon 10 of the HMBS gene, resulting in a leu177-to-arg (L177R) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1427766" 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="0026" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0026 PORPHYRIA, ACUTE INTERMITTENT</strong>
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HMBS, ARG201TRP
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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> rs118204109 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204109;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/rs118204109?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=rs118204109" 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=rs118204109" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000001527 OR RCV000432186 OR RCV004584591" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001527, RCV000432186, RCV004584591" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001527...</a>
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</span>
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<span class="mim-text-font">
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<p>In a patient with acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#35" class="mim-tip-reference" title="Lundin, G., Wedell, A., Thunell, S., Anvret, M. <strong>Two new mutations in the porphobilinogen deaminase gene and a screening method using PCR amplification of specific alleles.</strong> Hum. Genet. 93: 59-62, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8270256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8270256</a>] [<a href="https://doi.org/10.1007/BF00218914" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8270256">Lundin et al. (1994)</a> identified a c.601C-T transition in exon 10 of the HMBS gene, resulting in an arg201-to-trp (R201W) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8270256" 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="0027" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0027 PORPHYRIA, ACUTE INTERMITTENT</strong>
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HMBS, GLU223LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs118204110 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204110;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=rs118204110" 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=rs118204110" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000001532 OR RCV001209137" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001532, RCV001209137" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001532...</a>
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</span>
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<p>In a patient with CRM-negative acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#18" class="mim-tip-reference" title="Gu, X.-F., de Rooij, F., Voortman, G., te Velde, K., Deybach, J. C., Nordmann, Y., Grandchamp, B. <strong>Detection of eleven mutations causing acute intermittent porphyria using denaturing gradient gel electrophoresis.</strong> Hum. Genet. 93: 47-52, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8270254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8270254</a>] [<a href="https://doi.org/10.1007/BF00218912" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8270254">Gu et al. (1994)</a> identified a c.667G-A transition in exon 12 of the HMBS gene, resulting in a glu223-to-lys (E223K) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8270254" 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="0028" class="mim-anchor"></a>
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<h4>
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<strong>.0028 PORPHYRIA, ACUTE INTERMITTENT</strong>
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HMBS, 2-BP DEL, 730CT
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1565757839 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1565757839;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=rs1565757839" 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=rs1565757839" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000001533 OR RCV001389655" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001533, RCV001389655" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001533...</a>
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</span>
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<span class="mim-text-font">
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<p>In a patient with CRM-negative acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#41" class="mim-tip-reference" title="Mgone, C. S., Lanyon, W. G., Moore, M. R., Louie, G. V., Conner, J. M. <strong>Detection of a high mutation frequency in exon 12 of the porphobilinogen deaminase gene in patients with acute intermittent porphyria.</strong> Hum. Genet. 92: 619-622, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8262523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8262523</a>] [<a href="https://doi.org/10.1007/BF00420949" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8262523">Mgone et al. (1993)</a> and <a href="#18" class="mim-tip-reference" title="Gu, X.-F., de Rooij, F., Voortman, G., te Velde, K., Deybach, J. C., Nordmann, Y., Grandchamp, B. <strong>Detection of eleven mutations causing acute intermittent porphyria using denaturing gradient gel electrophoresis.</strong> Hum. Genet. 93: 47-52, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8270254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8270254</a>] [<a href="https://doi.org/10.1007/BF00218912" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8270254">Gu et al. (1994)</a> identified a 2-bp deletion (c.730delCT) exon 12 of the HMBS gene. This frameshift mutation leads to a premature termination 6 codons downstream and a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8262523+8270254" 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>.0029 PORPHYRIA, ACUTE INTERMITTENT</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">rs118204111 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204111;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=rs118204111" 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=rs118204111" 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=RCV000001534 OR RCV002298429" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001534, RCV002298429" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001534...</a>
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<p>In a patient with acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#41" class="mim-tip-reference" title="Mgone, C. S., Lanyon, W. G., Moore, M. R., Louie, G. V., Conner, J. M. <strong>Detection of a high mutation frequency in exon 12 of the porphobilinogen deaminase gene in patients with acute intermittent porphyria.</strong> Hum. Genet. 92: 619-622, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8262523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8262523</a>] [<a href="https://doi.org/10.1007/BF00420949" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8262523">Mgone et al. (1993)</a> identified a c.739T-C transition in exon 12 of the HMBS gene, resulting in a cys247-to-arg (C247R) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8262523" 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>.0030 PORPHYRIA, ACUTE INTERMITTENT</strong>
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HMBS, 8-BP INS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1565757857 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1565757857;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=rs1565757857" 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=rs1565757857" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000001535" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001535" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001535</a>
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<span class="mim-text-font">
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<p>In a patient with CRM-negative acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#18" class="mim-tip-reference" title="Gu, X.-F., de Rooij, F., Voortman, G., te Velde, K., Deybach, J. C., Nordmann, Y., Grandchamp, B. <strong>Detection of eleven mutations causing acute intermittent porphyria using denaturing gradient gel electrophoresis.</strong> Hum. Genet. 93: 47-52, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8270254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8270254</a>] [<a href="https://doi.org/10.1007/BF00218912" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8270254">Gu et al. (1994)</a> identified an 8-bp insertion at position c.742 of the coding sequence in exon 12 of the HMBS gene. This frameshift mutation leads to a premature termination 10 codons downstream and a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8270254" 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="0031" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0031 PORPHYRIA, ACUTE INTERMITTENT</strong>
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</h4>
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HMBS, GLU250LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs118204112 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204112;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=rs118204112" 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=rs118204112" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000001536" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001536" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001536</a>
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<span class="mim-text-font">
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<p>In a patient with CRM-negative acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#18" class="mim-tip-reference" title="Gu, X.-F., de Rooij, F., Voortman, G., te Velde, K., Deybach, J. C., Nordmann, Y., Grandchamp, B. <strong>Detection of eleven mutations causing acute intermittent porphyria using denaturing gradient gel electrophoresis.</strong> Hum. Genet. 93: 47-52, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8270254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8270254</a>] [<a href="https://doi.org/10.1007/BF00218912" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8270254">Gu et al. (1994)</a> identified a c.748G-A transition in exon 12 of the HMBS gene, resulting in a glu250-to-lys (E250K) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8270254" 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="0032" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0032 PORPHYRIA, ACUTE INTERMITTENT</strong>
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HMBS, ALA252THR
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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> rs118204113 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204113;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/rs118204113?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=rs118204113" 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=rs118204113" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000001537 OR RCV002512652" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001537, RCV002512652" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001537...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#41" class="mim-tip-reference" title="Mgone, C. S., Lanyon, W. G., Moore, M. R., Louie, G. V., Conner, J. M. <strong>Detection of a high mutation frequency in exon 12 of the porphobilinogen deaminase gene in patients with acute intermittent porphyria.</strong> Hum. Genet. 92: 619-622, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8262523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8262523</a>] [<a href="https://doi.org/10.1007/BF00420949" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8262523">Mgone et al. (1993)</a> identified a c.754G-A transition in exon 12 of the HMBS gene, resulting in an ala252-to-thr (A252T) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8262523" 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="0033" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0033 PORPHYRIA, ACUTE INTERMITTENT</strong>
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</h4>
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HMBS, ALA252VAL
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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> rs118204114 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204114;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/rs118204114?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=rs118204114" 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=rs118204114" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000001538" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001538" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001538</a>
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</span>
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<span class="mim-text-font">
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<p>In a patient with acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#41" class="mim-tip-reference" title="Mgone, C. S., Lanyon, W. G., Moore, M. R., Louie, G. V., Conner, J. M. <strong>Detection of a high mutation frequency in exon 12 of the porphobilinogen deaminase gene in patients with acute intermittent porphyria.</strong> Hum. Genet. 92: 619-622, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8262523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8262523</a>] [<a href="https://doi.org/10.1007/BF00420949" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8262523">Mgone et al. (1993)</a> identified a c.755C-T transition in exon 12 of the HMBS gene, resulting in an ala252-to-val (A252V) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8262523" 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="0034" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0034 PORPHYRIA, ACUTE INTERMITTENT</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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HMBS, HIS256ASN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs118204115 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204115;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=rs118204115" 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=rs118204115" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000001539" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001539" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001539</a>
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</span>
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</div>
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<span class="mim-text-font">
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<p>In a patient with acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#41" class="mim-tip-reference" title="Mgone, C. S., Lanyon, W. G., Moore, M. R., Louie, G. V., Conner, J. M. <strong>Detection of a high mutation frequency in exon 12 of the porphobilinogen deaminase gene in patients with acute intermittent porphyria.</strong> Hum. Genet. 92: 619-622, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8262523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8262523</a>] [<a href="https://doi.org/10.1007/BF00420949" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8262523">Mgone et al. (1993)</a> identified a c.766C-A transversion in exon 12 of the HMBS gene, resulting in a his256-to-asn (H256N) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8262523" 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="0035" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0035 PORPHYRIA, ACUTE INTERMITTENT</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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<div style="float: left;">
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HMBS, IVS12DS, G-C, +1
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1565758008 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1565758008;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=rs1565758008" 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=rs1565758008" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000001540" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001540" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001540</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a Japanese patient with acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#6" class="mim-tip-reference" title="Daimon, M., Yamatani, K., Igarashi, M., Fukase, N., Ogawa, A., Tominaga, M., Sasaki, H. <strong>Acute intermittent porphyria caused by a G to C mutation in exon 12 of the porphobilinogen deaminase gene that results in exon skipping.</strong> Hum. Genet. 92: 549-553, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8262514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8262514</a>] [<a href="https://doi.org/10.1007/BF00420937" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8262514">Daimon et al. (1993)</a> identified a c.771G-C transversion in the first nucleotide of the donor site of intron 12 of the HMBS gene, resulting in aberrant splicing and the skipping of exon 12. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8262514" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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</div>
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</div>
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<div>
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<div>
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<a id="0036" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0036 PORPHYRIA, ACUTE INTERMITTENT</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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<div style="float: left;">
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HMBS, IVS14DS, G-A, +1
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1946325053 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1946325053;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=rs1946325053" 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=rs1946325053" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000001541 OR RCV001851551" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001541, RCV001851551" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001541...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with CRM-negative acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#17" class="mim-tip-reference" title="Gu, X.-F., de Rooij, F., Lee, J. S., te Velde, K., Deybach, J.-C., Nordmann, Y., Grandchamp, B. <strong>High prevalence of a point mutation in the porphobilinogen deaminase gene in Dutch patients with acute intermittent porphyria.</strong> Hum. Genet. 91: 128-130, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8096492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8096492</a>] [<a href="https://doi.org/10.1007/BF00222712" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8096492">Gu et al. (1993)</a> identified a c.912G-A transition in the first nucleotide of the donor splice site of intron 14 of the HMBS gene, resulting in abnormal splicing and the skipping of exon 14. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8096492" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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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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<a id="0037" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0037 PORPHYRIA, ACUTE INTERMITTENT</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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<div style="float: left;">
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HMBS, IVS6DS, G-C, +1
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1565754565 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1565754565;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=rs1565754565" 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=rs1565754565" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
|
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000001542" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001542" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001542</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of 28 Swedish families with CRM-negative acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#34" class="mim-tip-reference" title="Lundin, G., Lee, J.-S., Thunell, S., Anvret, M. <strong>Genetic investigation of the porphobilinogen deaminase gene in Swedish acute intermittent porphyria families.</strong> Hum. Genet. 100: 63-66, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9225970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9225970</a>] [<a href="https://doi.org/10.1007/s004390050466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9225970">Lundin et al. (1997)</a> identified a G-to-C transversion at the splice donor site of intron 6 of the HMBS gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9225970" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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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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<a id="0038" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0038 PORPHYRIA, ACUTE INTERMITTENT</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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<div style="float: left;">
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HMBS, GLY216ASP
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs118204116 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204116;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=rs118204116" 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=rs118204116" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000001543 OR RCV001851552" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001543, RCV001851552" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001543...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a Swedish family with CRM-negative acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#34" class="mim-tip-reference" title="Lundin, G., Lee, J.-S., Thunell, S., Anvret, M. <strong>Genetic investigation of the porphobilinogen deaminase gene in Swedish acute intermittent porphyria families.</strong> Hum. Genet. 100: 63-66, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9225970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9225970</a>] [<a href="https://doi.org/10.1007/s004390050466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9225970">Lundin et al. (1997)</a> identified a c.646G-A transition in exon 11 of the HMBS gene, resulting in a gly216-to-asp (G216D) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9225970" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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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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<a id="0039" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0039 PORPHYRIA, ACUTE INTERMITTENT</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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<div style="float: left;">
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HMBS, 2-BP DEL, 847TG
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1592220835 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1592220835;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=rs1592220835" 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=rs1592220835" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000001544" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001544" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001544</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a Swedish family with acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#34" class="mim-tip-reference" title="Lundin, G., Lee, J.-S., Thunell, S., Anvret, M. <strong>Genetic investigation of the porphobilinogen deaminase gene in Swedish acute intermittent porphyria families.</strong> Hum. Genet. 100: 63-66, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9225970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9225970</a>] [<a href="https://doi.org/10.1007/s004390050466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9225970">Lundin et al. (1997)</a> identified a 2-bp deletion (c.847delTG) in exon 14 of the HMBS gene, resulting in an mRNA translational frameshift. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9225970" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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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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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000001545" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001545" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001545</a>
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<p><a href="#42" class="mim-tip-reference" title="Mustajoki, S., Ahola, H., Mustajoki, P., Kauppinen, R. <strong>Insertion of Alu element responsible for acute intermittent porphyria.</strong> Hum. Mutat. 13: 431-438, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10408772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10408772</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1999)13:6<431::AID-HUMU2>3.0.CO;2-Y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10408772">Mustajoki et al. (1999)</a> reported a large Finnish family in which an Alu element interfered with the coding region of the PBGD gene, resulting in acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>). A 333-bp Alu sequence was directly inserted into exon 5 in antisense orientation. <a href="#42" class="mim-tip-reference" title="Mustajoki, S., Ahola, H., Mustajoki, P., Kauppinen, R. <strong>Insertion of Alu element responsible for acute intermittent porphyria.</strong> Hum. Mutat. 13: 431-438, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10408772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10408772</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1999)13:6<431::AID-HUMU2>3.0.CO;2-Y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10408772">Mustajoki et al. (1999)</a> noted that this Alu cassette belongs to a Ya5 subfamily, one of the evolutionarily youngest and at that time most active Alu subfamilies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10408772" 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>.0041 PORPHYRIA, ACUTE INTERMITTENT, NONERYTHROID VARIANT</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000001546" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001546" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001546</a>
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<p><a href="#57" class="mim-tip-reference" title="Whatley, S. D., Roberts, A. G., Llewellyn, D. H., Bennett, C. P., Garrett, C., Elder, G. H. <strong>Non-erythroid form of acute intermittent porphyria caused by promoter and frameshift mutations distant from the coding sequence of exon 1 of the HMBS gene.</strong> Hum. Genet. 107: 243-248, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11071386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11071386</a>] [<a href="https://doi.org/10.1007/s004390000356" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11071386">Whatley et al. (2000)</a> identified a 1-bp deletion (-154delG) in the promoter region of the HMBS gene as the cause of the nonerythroid variant of acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>). Reporter gene and electromobility shift assays showed that the G nucleotide at position -154, the most 5-prime of several transcription initiation sites in the ubiquitous HMBS promoter, which lies immediately 3-prime to a transcription factor IIB binding motif, is essential for normal transcription. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11071386" 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>.0042 PORPHYRIA, ACUTE INTERMITTENT, NONERYTHROID VARIANT</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">rs1592212904 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1592212904;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=rs1592212904" 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=rs1592212904" 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=RCV000001547" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001547" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001547</a>
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<p><a href="#57" class="mim-tip-reference" title="Whatley, S. D., Roberts, A. G., Llewellyn, D. H., Bennett, C. P., Garrett, C., Elder, G. H. <strong>Non-erythroid form of acute intermittent porphyria caused by promoter and frameshift mutations distant from the coding sequence of exon 1 of the HMBS gene.</strong> Hum. Genet. 107: 243-248, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11071386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11071386</a>] [<a href="https://doi.org/10.1007/s004390000356" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11071386">Whatley et al. (2000)</a> identified a 1-bp deletion (c.41delA) in exon 3 of the HMBS gene as the cause of the nonerythroid variant of acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>). The frameshift mutation introduced a stop codon into mRNA for the ubiquitous isoform only. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11071386" 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>.0043 PORPHYRIA, ACUTE INTERMITTENT</strong>
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HMBS, TRP283TER
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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> rs118204117 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204117;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/rs118204117?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=rs118204117" 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=rs118204117" 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=RCV000001548 OR RCV000418446" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001548, RCV000418446" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001548...</a>
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<p>In a patient with acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#3" class="mim-tip-reference" title="Chen, C. H., Astrin, K. H., Lee, G., Anderson, K. E., Desnick, R. J. <strong>Acute intermittent porphyria: identification and expression of exonic mutations in the hydroxymethylbilane synthase gene: an initiation codon missense mutation in the housekeeping transcript causes 'variant acute intermittent porphyria' with normal expression of the erythroid-specific enzyme.</strong> J. Clin. Invest. 94: 1927-1937, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7962538/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7962538</a>] [<a href="https://doi.org/10.1172/JCI117543" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7962538">Chen et al. (1994)</a> identified a heterozygous c.848G-A transition in exon 14 of the HMBS gene, resulting in a trp283-to-ter (W283X) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7962538" 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>Nearly 60% of all Swiss AIP patients carry the W283X mutation. In France, the prevalence of W283X is less than 5% (<a href="#50" class="mim-tip-reference" title="Schneider-Yin, X., Hergersberg, M., Goldgar, D. E., Rufenacht, U. B., Schuurmans, M. M., Puy, H., Deybach, J.-C., Minder, E. I. <strong>Ancestral founder of mutation W283X in the porphobilinogen deaminase gene among acute intermittent porphyria patients.</strong> Hum. Hered. 54: 69-81, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12566739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12566739</a>] [<a href="https://doi.org/10.1159/000067665" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12566739">Schneider-Yin et al., 2002</a>). In 12 of 25 AIP families of Swiss and French origin, <a href="#50" class="mim-tip-reference" title="Schneider-Yin, X., Hergersberg, M., Goldgar, D. E., Rufenacht, U. B., Schuurmans, M. M., Puy, H., Deybach, J.-C., Minder, E. I. <strong>Ancestral founder of mutation W283X in the porphobilinogen deaminase gene among acute intermittent porphyria patients.</strong> Hum. Hered. 54: 69-81, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12566739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12566739</a>] [<a href="https://doi.org/10.1159/000067665" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12566739">Schneider-Yin et al. (2002)</a> identified a common haplotype containing the W283X HMBS mutation. The authors suggested that a single mutational event took place approximately 40 generations ago (i.e., 1,000 years ago). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12566739" 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>.0044 PORPHYRIA, ACUTE INTERMITTENT, NONERYTHROID VARIANT</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">rs118204118 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204118;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=rs118204118" 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=rs118204118" 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=RCV000001549 OR RCV001851553" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001549, RCV001851553" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001549...</a>
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<p>In a patient with the nonerythroid variant of acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#3" class="mim-tip-reference" title="Chen, C. H., Astrin, K. H., Lee, G., Anderson, K. E., Desnick, R. J. <strong>Acute intermittent porphyria: identification and expression of exonic mutations in the hydroxymethylbilane synthase gene: an initiation codon missense mutation in the housekeeping transcript causes 'variant acute intermittent porphyria' with normal expression of the erythroid-specific enzyme.</strong> J. Clin. Invest. 94: 1927-1937, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7962538/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7962538</a>] [<a href="https://doi.org/10.1172/JCI117543" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7962538">Chen et al. (1994)</a> identified a heterozygous c.3G-A transition in exon 1 of the HMBS gene, resulting in a met1-to-val (M1V) substitution in the initiation of translation codon for the housekeeping transcript. Thus, translation of the erythrocyte transcript was unaffected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7962538" 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>.0045 ENCEPHALOPATHY, PORPHYRIA-RELATED</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">rs118204119 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204119;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=rs118204119" 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=rs118204119" 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=RCV003764513" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003764513" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003764513</a>
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<p>In a 7-year-old boy, born of consanguineous Turkish parents, with porphyria-related encephalopathy (ENCEP; <a href="/entry/620704">620704</a>), <a href="#21" class="mim-tip-reference" title="Hessels, J., Voortman, G., van der Wagen, A., van der Elzen, C., Scheffer, H., Zuijderhoudt, F. M. J. <strong>Homozygous acute intermittent porphyria in a 7-year-old boy with massive excretions of porphyrins and porphyrin precursors.</strong> J. Inherit. Metab. Dis. 27: 19-27, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14970743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14970743</a>] [<a href="https://doi.org/10.1023/B:BOLI.0000016613.75677.05" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14970743">Hessels et al. (2004)</a> identified a homozygous leu81-to-pro (L81P) substitution in exon 6 of the HMBS gene. Porphobilinogen activity in red cells was decreased to 2 to 4%. Both parents were heterozygous and asymptomatic. Leu81 in PBG deaminase is an evolutionarily conserved residue in the second alpha helix, suggesting its structural importance for preservation of enzyme activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14970743" 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">rs118204120 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118204120;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=rs118204120" 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=rs118204120" 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=RCV000001551 OR RCV001389642 OR RCV003924793" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001551, RCV001389642, RCV003924793" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001551...</a>
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<p>In affected members of 2 Finnish families with acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>), <a href="#23" class="mim-tip-reference" title="Kauppinen, R., Mustajoki, S., Pihlaja, H., Peltonen, L., Mustajoki, P. <strong>Acute intermittent porphyria in Finland: 19 mutations in the porphobilinogen deaminase gene.</strong> Hum. Molec. Genet. 4: 215-222, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7757070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7757070</a>] [<a href="https://doi.org/10.1093/hmg/4.2.215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7757070">Kauppinen et al. (1995)</a> identified a heterozygous c.445C-T transition in exon 9 of the HMBS gene, resulting in an arg149-to-ter (R149X) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7757070" 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="#46" class="mim-tip-reference" title="Poblete-Gutierrez, P., Wiederholt, T., Martinez-Mir, A., Merk, H. F., Connor, J. M., Christiano, A. M., Frank, J. <strong>Demystification of Chester porphyria: a nonsense mutation in the porphobilinogen deaminase gene.</strong> Physiol. Res. 55 (Suppl. 2): S137-S144, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17298217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17298217</a>] [<a href="https://doi.org/10.33549/physiolres.930000.55.S2.137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17298217">Poblete-Gutierrez et al. (2006)</a> identified a heterozygous R149X substitution in affected members of the original family with so-called 'Chester type porphyria' (<a href="#36" class="mim-tip-reference" title="McColl, K. E. L., Thompson, G. G., Moore, M. R., Goldberg, A., Church, S. E., Qadiri, M. R., Youngs, G. R. <strong>Chester porphyria: biochemical studies of a new form of acute porphyria.</strong> Lancet 326: 796-799, 1985. Note: Originally Volume II.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2864531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2864531</a>] [<a href="https://doi.org/10.1016/s0140-6736(85)90793-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2864531">McColl et al., 1985</a>) (see <a href="/entry/176000">176000</a>). The mutation was not found in 200 control chromosomes. The family had originally been reported as having features of both AIP and variegated porphyria (VP; <a href="/entry/176200">176200</a>), but no mutations in the PPOX gene (<a href="/entry/600923">600923</a>) were identified. The mutation occurred at a hypermutable CpG dinucleotide. The findings confirmed that Chester type porphyria is a variant of AIP. <a href="#46" class="mim-tip-reference" title="Poblete-Gutierrez, P., Wiederholt, T., Martinez-Mir, A., Merk, H. F., Connor, J. M., Christiano, A. M., Frank, J. <strong>Demystification of Chester porphyria: a nonsense mutation in the porphobilinogen deaminase gene.</strong> Physiol. Res. 55 (Suppl. 2): S137-S144, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17298217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17298217</a>] [<a href="https://doi.org/10.33549/physiolres.930000.55.S2.137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17298217">Poblete-Gutierrez et al. (2006)</a> suggested that the original biochemical studies indicating PPOX deficiency may have been erroneous or misinterpreted. A different mutation in this codon has also been associated with AIP (R149Q; <a href="#0008">609806.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2864531+17298217" 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>.0047 LEUKOENCEPHALOPATHY, PORPHYRIA-RELATED</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> rs142459647 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs142459647;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/rs142459647?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=rs142459647" 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=rs142459647" 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=RCV000148511 OR RCV000498317 OR RCV003764896" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000148511, RCV000498317, RCV003764896" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000148511...</a>
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<p>In 3 adult sibs, born of unrelated Dutch parents, with slowly progressive porphyria-related leukoencephalopathy (LENCEP; <a href="/entry/620711">620711</a>), <a href="#25" class="mim-tip-reference" title="Kevelam, S. H., Neeleman, R. A., Waisfisz, Q., Friesema, E. C. H., Langendonk, J. G., van der Knaap, M. S. <strong>Acute intermittent porphyria-related leukoencephalopathy.</strong> Neurology 87: 1258-1265, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27558376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27558376</a>] [<a href="https://doi.org/10.1212/WNL.0000000000003129" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27558376">Kevelam et al. (2016)</a> identified compound heterozygous missense mutations in the HMBS gene: a c.674G-A transition in exon 12, resulting in an arg225-to-gln (R225Q) substitution, and R167Q (<a href="#0005">609806.0005</a>). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. HMBS erythrocyte activity ranged from 55 to 67% of normal controls in the affected sibs, similar to heterozygous carriers of HMBS mutations. At least 2 unaffected sibs carried a heterozygous R225Q variant; HMBS activity was 83% of controls in 1 and 105% of controls in the other. Urine and plasma PBG were mildly elevated (2- to 4-fold increase in urine) in the affected sibs, but not in the unaffected carrier sibs. Plasma ALA levels were borderline elevated in both affected and unaffected sibs. <a href="#25" class="mim-tip-reference" title="Kevelam, S. H., Neeleman, R. A., Waisfisz, Q., Friesema, E. C. H., Langendonk, J. G., van der Knaap, M. S. <strong>Acute intermittent porphyria-related leukoencephalopathy.</strong> Neurology 87: 1258-1265, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27558376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27558376</a>] [<a href="https://doi.org/10.1212/WNL.0000000000003129" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27558376">Kevelam et al. (2016)</a> noted that both the R225Q and R167Q mutations had been reported in the heterozygous state in patients with autosomal dominant acute intermittent porphyria (AIP; <a href="/entry/176000">176000</a>). The authors concluded that either the mildly reduced enzyme activity with mildly elevated ALA and PBG did not cause the chronic leukoencephalopathy observed in the 3 sibs with biallelic variants, or that the enzyme activity in erythrocytes does not reflect enzyme activity in the brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27558376" 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 45-year-old man (P3), born of unrelated Dutch parents (family 2), with LENCEP, <a href="#53" class="mim-tip-reference" title="Stutterd, C. A., Kidd, A., Florkowski, C., Janus, E., Fanjul, M., Raizis, A., Wu, T. Y., Archer, J., Leventer, R. J., Amor, D. J., Lukic, V., Bahlo, M., Gow, P., Lockhart, P. J., van der Knaap, M. S., Delatycki, M. B. <strong>Expanding the clinical and radiological phenotypes of leukoencephalopathy due to biallelic HMBS mutations.</strong> Am. J. Med. Genet. 185A: 2941-2950, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34089223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34089223</a>] [<a href="https://doi.org/10.1002/ajmg.a.62377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34089223">Stutterd et al. (2021)</a> identified compound heterozygosity for the R225Q (c.674G-A, NM_000190.3) and R167Q mutations. His mother, who was heterozygous for the R167Q mutation, had latent AIP; his father was unavailable for testing. A measurement of HMBS enzyme activity was not available for P3. <a href="#53" class="mim-tip-reference" title="Stutterd, C. A., Kidd, A., Florkowski, C., Janus, E., Fanjul, M., Raizis, A., Wu, T. Y., Archer, J., Leventer, R. J., Amor, D. J., Lukic, V., Bahlo, M., Gow, P., Lockhart, P. J., van der Knaap, M. S., Delatycki, M. B. <strong>Expanding the clinical and radiological phenotypes of leukoencephalopathy due to biallelic HMBS mutations.</strong> Am. J. Med. Genet. 185A: 2941-2950, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34089223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34089223</a>] [<a href="https://doi.org/10.1002/ajmg.a.62377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34089223">Stutterd et al. (2021)</a> noted that the pathogenicity of the R225Q variant has not been conclusively demonstrated and that previous functional studies have yielded conflicting results of the effect of this variant on HMBS enzyme activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34089223" 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 2 adult sibs, born of consanguineous Lebanese parents (family 1), with slowly progressive porphyria-related leukoencephalopathy (LENCEP; <a href="/entry/620711">620711</a>), <a href="#53" class="mim-tip-reference" title="Stutterd, C. A., Kidd, A., Florkowski, C., Janus, E., Fanjul, M., Raizis, A., Wu, T. Y., Archer, J., Leventer, R. J., Amor, D. J., Lukic, V., Bahlo, M., Gow, P., Lockhart, P. J., van der Knaap, M. S., Delatycki, M. B. <strong>Expanding the clinical and radiological phenotypes of leukoencephalopathy due to biallelic HMBS mutations.</strong> Am. J. Med. Genet. 185A: 2941-2950, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34089223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34089223</a>] [<a href="https://doi.org/10.1002/ajmg.a.62377" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34089223">Stutterd et al. (2021)</a> identified a homozygous c.251C-A transversion (c.251C-A, NM_000190.3) in the HMBS gene, resulting in an ala84-to-asp (A84D) substitution at a conserved residue in the second alpha-helix. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not present in the gnomAD database. Erythrocyte HMBS enzyme activity ranged from 13 to 18% of normal control values in the sibs. HMBS erythrocyte activity in an unaffected sib who was heterozygous for the mutation was 50% of normal. The patients had onset of progressive neurologic symptoms in the first decade. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34089223" 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="#Llewellyn1987" class="mim-tip-reference" title="Llewellyn, D. H., Elder, G. H., Kalsheker, N. A., Marsh, O. W. M., Harrison, P. R., Grandchamp, B., Picat, C., Nordmann, Y., Romeo, P. H., Goossens, M. <strong>DNA polymorphism of human porphobilinogen deaminase gene in acute intermittent porphyria.</strong> Lancet 330: 706-708, 1987. Note: Originally Volume 2.">Llewellyn et al. (1987)</a>
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[<a href="https://doi.org/10.1073/pnas.85.1.6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddp525" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00420937" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00303004" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI114869" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1034/j.1399-0004.2002.620406.x" target="_blank">Full Text</a>]
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<a id="Grandchamp1987" class="mim-anchor"></a>
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<div class="">
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[<a href="https://doi.org/10.1111/j.1432-1033.1987.tb10548.x" target="_blank">Full Text</a>]
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<a id="Grandchamp1990" class="mim-anchor"></a>
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<div class="">
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Grandchamp, B., Delfau, M. H., Picat, C., de Rooij, F. W. M., Nordmann, Y.
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<a id="Grandchamp1989" class="mim-anchor"></a>
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Grandchamp, B., Picat, C., de Rooij, F., Beaumont, C., Wilson, P., Deybach, J. C., Nordmann, Y.
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<strong>A point mutation G-to-A in exon 12 of the porphobilinogen deaminase gene results in exon skipping and is responsible for acute intermittent porphyria.</strong>
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[<a href="https://doi.org/10.1093/nar/17.16.6637" target="_blank">Full Text</a>]
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<a id="Grandchamp1989" class="mim-anchor"></a>
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Grandchamp, B., Picat, C., Kauppinen, R., Mignotte, V., Peltonen, L., Mustajoki, P., Romeo, P. H., Goossens, M., Nordmann, Y.
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<strong>Molecular analysis of acute intermittent porphyria in a Finnish family with normal erythrocyte porphobilinogen deaminase.</strong>
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[<a href="https://doi.org/10.1111/j.1365-2362.1989.tb00252.x" target="_blank">Full Text</a>]
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<a id="Grandchamp1989" class="mim-anchor"></a>
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Grandchamp, B., Picat, C., Mignotte, V., Wilson, J. H. P., te Velde, K., Sandkuyl, L., Romeo, P. H., Goossens, M., Nordmann, Y.
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[<a href="https://doi.org/10.1073/pnas.86.2.661" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00222712" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00218912" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1182/blood.v97.3.815" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1023/B:BOLI.0000016613.75677.05" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddv222" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.1380010508" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.88.23.10912" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s004390050466" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00218914" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1159/000131637" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00210738" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00420949" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(1999)13:6<431::AID-HUMU2>3.0.CO;2-Y" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2227955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2227955</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2227955" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/BF00193588" target="_blank">Full Text</a>]
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<a id="52" class="mim-anchor"></a>
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<a id="Solis2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Solis, C., Martinez-Bermejo, A., Naidich, T. P., Kaufmann, W. E., Astrin, K. H., Bishop, D. F., Desnick, R. J.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15534187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15534187</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15534187" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1001/archneur.61.11.1764" target="_blank">Full Text</a>]
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<a id="Stutterd2021" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Stutterd, C. A., Kidd, A., Florkowski, C., Janus, E., Fanjul, M., Raizis, A., Wu, T. Y., Archer, J., Leventer, R. J., Amor, D. J., Lukic, V., Bahlo, M., Gow, P., Lockhart, P. J., van der Knaap, M. S., Delatycki, M. B.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34089223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34089223</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34089223" 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/ajmg.a.62377" target="_blank">Full Text</a>]
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<li>
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<a id="54" class="mim-anchor"></a>
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<a id="Tunnacliffe1990" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tunnacliffe, A., McGuire, R. S.
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<strong>A physical linkage group in human chromosome band 11q23 covering a region implicated in leukocyte neoplasia.</strong>
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[<a href="https://doi.org/10.1016/0888-7543(90)90030-x" target="_blank">Full Text</a>]
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<a id="55" class="mim-anchor"></a>
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<a id="Vidaud1989" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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<strong>A 5-prime splice-region G-to-C mutation in exon 1 of the human beta-globin gene inhibits pre-mRNA splicing: a mechanism for beta(+)-thalassemia.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2915972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2915972</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2915972" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.86.3.1041" target="_blank">Full Text</a>]
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<a id="56" class="mim-anchor"></a>
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<a id="Wang1981" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wang, A.-L., Arredondo-Vega, F. X., Giampietro, P. F., Smith, M., Anderson, W. F., Desnick, R. J.
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<strong>Regional gene assignment of human porphobilinogen deaminase and esterase A(4) to chromosome 11q23-11qter.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6946513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6946513</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6946513" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.78.9.5734" target="_blank">Full Text</a>]
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<a id="57" class="mim-anchor"></a>
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<a id="Whatley2000" class="mim-anchor"></a>
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<p class="mim-text-font">
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Whatley, S. D., Roberts, A. G., Llewellyn, D. H., Bennett, C. P., Garrett, C., Elder, G. H.
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<strong>Non-erythroid form of acute intermittent porphyria caused by promoter and frameshift mutations distant from the coding sequence of exon 1 of the HMBS gene.</strong>
|
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Hum. Genet. 107: 243-248, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11071386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11071386</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11071386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s004390000356" target="_blank">Full Text</a>]
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<a id="Whatley1999" class="mim-anchor"></a>
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Whatley, S. D., Woolf, J. R., Elder, G. H.
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<strong>Comparison of complementary and genomic DNA sequencing for the detection of mutations in the HMBS gene in British patients with acute intermittent porphyria: identification of 25 novel mutations.</strong>
|
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Hum. Genet. 104: 505-510, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10453740/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10453740</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10453740" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s004390050995" target="_blank">Full Text</a>]
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<a id="59" class="mim-anchor"></a>
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<a id="Yasuda2019" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yasuda, M., Gan, L., Chen, B., Yu, C., Zhang, J., Gama-Sosa, M. A., Pollak, D. D., Berger, S., Phillips, J. D., Edelmann, W., Desnick, R. J.
|
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<strong>Homozygous hydroxymethylbilane synthase knock-in mice provide pathogenic insights into the severe neurological impairments present in human homozygous dominant acute intermittent porphyria.</strong>
|
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Hum. Molec. Genet. 28: 1755-1767, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30615115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30615115</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30615115[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30615115" 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/ddz003" target="_blank">Full Text</a>]
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<a id="60" class="mim-anchor"></a>
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<a id="Yasuda2020" class="mim-anchor"></a>
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<p class="mim-text-font">
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Yasuda, M.
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<strong>Personal Communication.</strong>
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New York, N.Y. 10/21/2020.
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</p>
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</ol>
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<div>
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<br />
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</div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 02/08/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 10/29/2020<br>Patricia A. Hartz - updated : 2/26/2016<br>George E. Tiller - updated : 2/8/2011<br>Cassandra L. Kniffin - updated : 5/22/2009<br>Ada Hamosh - updated : 7/31/2007
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</span>
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</div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin : 12/22/2005
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</span>
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<a id="editHistory" class="mim-anchor"></a>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 02/20/2024
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</span>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 02/19/2024<br>ckniffin : 02/08/2024<br>carol : 10/31/2020<br>carol : 10/29/2020<br>mgross : 02/26/2016<br>mgross : 2/26/2016<br>carol : 3/11/2015<br>carol : 2/25/2015<br>wwang : 3/11/2011<br>terry : 2/8/2011<br>wwang : 6/3/2009<br>ckniffin : 5/22/2009<br>terry : 4/13/2009<br>alopez : 8/3/2007<br>terry : 7/31/2007<br>carol : 1/5/2006<br>ckniffin : 1/4/2006<br>ckniffin : 12/28/2005
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</span>
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<div class="container visible-print-block">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 609806
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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HYDROXYMETHYLBILANE SYNTHASE; HMBS
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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PORPHOBILINOGEN DEAMINASE; PBGD<br />
|
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PRE-UROPORPHYRINOGEN SYNTHASE<br />
|
|
UROPORPHYRINOGEN I SYNTHASE<br />
|
|
UROPORPHYRINOGEN I SYNTHETASE
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: HMBS</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 234422006;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
|
Cytogenetic location: 11q23.3
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 11:119,084,881-119,093,549 </span>
|
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</em>
|
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</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
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<th>
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Phenotype
|
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</th>
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
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</thead>
|
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<tbody>
|
|
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<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
11q23.3
|
|
</span>
|
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</td>
|
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|
|
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<td>
|
|
<span class="mim-font">
|
|
Encephalopathy, porphyria-related
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
620704
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
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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>
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<span class="mim-font">
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Leukoencephalopathy, porphyria-related
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
620711
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Porphyria, acute intermittent
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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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176000
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Porphyria, acute intermittent, nonerythroid variant
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</span>
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</td>
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<td>
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|
<span class="mim-font">
|
|
176000
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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|
3
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|
</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</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>Porphobilinogen deaminase (PBGD; EC 4.3.1.8) is the third enzyme of the biosynthetic pathway leading to the production of heme. It catalyzes the synthesis of hydroxymethylbilane by stepwise condensation of 4 porphobilinogen units. Hydroxymethylbilane is then converted to uroporphyrinogen III by uroporphyrinogen III synthetase (UROS; 606938) (Raich et al., 1986). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Raich et al. (1986) isolated a cDNA clone corresponding to the human erythrocyte porphobilinogen deaminase gene from a human erythrocyte library prepared from human spleen. The deduced 334-amino acid protein has a calculated molecular mass of approximately 37.6 kD. Northern blot analysis identified a single 1.6-kb mRNA transcript. </p><p>Grandchamp et al. (1987) determined that there are 2 PBGD isoforms that differ by approximately 2 kD (40 and 42 kD). One is active in all tissues and can be isolated from liver, and the other is restricted to erythrocytes. The nonerythrocyte isoform contains an additional 17 amino acid residues at the N terminus. </p><p>Chretien et al. (1988) demonstrated that the PBGD gene undergoes alternative splicing with 2 different promoters to yield 2 mRNAs. The first 'upstream' promoter is active in all tissues and has structural features of a housekeeping promoter, whereas the second promoter, located 3 kb downstream, is active only in erythrocytes and shows structural homology to the beta-globin gene (141900) promoters. The 2 mRNAs differ only in their first exon. </p><p>Gubin and Miller (2001) identified 2 alternatively spliced isoforms of erythroid PBGD in CD34+/- (142230) erythroid precursor cells. Complete sequencing showed that the alternatively spliced form, designated PBGD-EA, contained the intron between exons 2 and 3, thus extending the 5-prime untranslated region of the erythroid transcript by 176 bp. Northern blot analysis identified a distinct 1.5-kb mRNA corresponding to the alternatively spliced erythrocyte isoform only in bone marrow and fetal spleen. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Chretien et al. (1988) determined that the HMBS gene contains 15 exons and spans approximately 10 kb of DNA. </p><p>The housekeeping HMBS transcript contains exons 1 and 3-15; the erythroid HMBS transcript is encoded by exons 2-15 (Chen et al., 1994). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By study of mouse-human hybrid clones, Meisler et al. (1980, 1981) showed that PBG-deaminase is determined by a gene on chromosome 11; Wang et al. (1981) assigned the locus to the long arm in the segment 11q23-qter. In 3 children with trisomy of 11qter, de Verneuil et al. (1982) studied expression of uroporphyrinogen I synthase. Dosage effect supported assignment to the region 11q23.2-qter. </p><p>By in situ hybridization and by gene dosage studies in patients with monosomy or trisomy of the terminal portion of 11q, Namba et al. (1991) refined the assignment of the PBGD gene to 11q24.1-q24.2. </p><p>Tunnacliffe and McGuire (1990) constructed a long-range restriction map extending over 1.8 Mb of 11q23.3 using pulsed field gel electrophoresis and concluded that PBGD is situated in the following relation to 5 other genes: cen--CD3E--CD3D--CD3G--PBGD--CBL2--THY1--qter. They determined that the CD3G (186740) gene and PBGD are separated by 750 kb. </p>
|
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Biochemical Features</strong>
|
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</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>By the method of isoelectric focusing, Meisler and Carter (1980) identified structural variants of PBG-deaminase. </p><p>Louie et al. (1992) defined the 3-domain structure of PBGD by x-ray analysis. Two of the domains structurally resembled the transferrins (see, e.g., TF; 190000). The x-ray structure and results from site-directed mutagenesis provided evidence for a single catalytic site. </p>
|
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</span>
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<div>
|
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<br />
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>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>Autosomal Dominant Acute Intermittent Porphyria</em></strong></p><p>
|
|
In a large Dutch family with the nonerythroid variant of acute intermittent porphyria (AIP; 176000), Grandchamp et al. (1989) identified a heterozygous splice site mutation in intron 1 of the PBGD gene (609806.0001). The mutation interrupted the sequence coding for the nonerythroid isoform of PBGD; thus, expression of the erythroid isoform was unaffected. In a patient with CRM-positive AIP, Grandchamp et al. (1989) identified a heterozygous mutation in the HMBS gene, resulting in the skipping of exon 12 (609806.0002). </p><p>In affected members of 11 different families with either CRM-negative or CRM-positive AIP, Grandchamp et al. (1990) identified 7 different point mutations in the PBGD gene.</p><p>In a patient with the nonerythroid variant of AIP, Chen et al. (1994) identified a mutation in the initiation codon of the housekeeping HMBS isoform (M1V; 609806.0044). Puy et al. (1998) identified 3 different mutations in the donor splice site of the HMBS gene in 4 unrelated patients with the nonerythroid variant of AIP. They found that the splice site mutations resulted in activation of a cryptic splice site located 67 nucleotides downstream from the normal splice site, leading to a frameshift and premature stop codon in exon 4. </p><p>In 28 Finnish families representing 72% of all AIP families in the Finnish population of 5 million, Kauppinen et al. (1995) found 19 separate mutations in HMBS: 13 novel mutations, including 1 de novo event, and 6 previously characterized mutations. </p><p>Whatley et al. (1999) found 39 different mutations in the HMBS gene in 54 of 57 consecutive patients with AIP. </p><p>In patients with the nonerythroid variant of AIP, Whatley et al. (2000) identified mutations in the housekeeping promoter (-154delG; 609806.0041) and in exon 3 (41delA; 609806.0042) of the HMBS gene. </p><p>Floderus et al. (2002) studied most of the AIP kindreds in Sweden. They identified 27 novel mutations in the HMBS gene, bringing the total number of known mutations in the HMBS gene in Sweden to 39. Most of the mutations were located in exons 10 and 12, with fewer in exon 7. Floderus et al. (2002) used the 3-dimensional structure of the porphobilinogen deaminase enzyme to predict the possible molecular and functional consequences of the novel Swedish missense and nonsense mutations. </p><p><strong><em>Porphyria-Related Encephalopathy</em></strong></p><p>
|
|
In a Dutch girl with porphyria-related encephalopathy (ENCEP; 620704) originally reported by Beukeveld et al. (1990), Picat et al. (1990) identified compound heterozygous missense mutations in the HMBS gene (R167Q, 609806.0005 and R173Q, 609806.0006). Each parent who had classic AIP was heterozygous for 1 of the mutations. The patient had a severe disease course and died at 8 years of age. </p><p>In an English brother and sister with ENCEP, Llewellyn et al. (1992) identified compound heterozygous missense mutations in the HMBS gene (R167Q and R167W, 609806.0013). </p><p>Solis et al. (2004) reported a Spanish patient with ENCEP who was homozygous for the R167W substitution. Both parents were heterozygous for the mutation. </p><p>In a patient, born of consanguineous Turkish parents, with ENCEP, Hessels et al. (2004) detected a homozygous missense mutation in the HMBS gene (L81P; 609806.0045). Porphobilinogen deaminase activity in red cells was decreased to 2 to 4%. The clinically unaffected parents were heterozygous for the mutation. </p><p><strong><em>Porphyria-Related Leukoencephalopathy</em></strong></p><p>
|
|
In 3 adult sibs, born of unrelated Dutch parents, with slowly progressive porphyria-related leukoencephalopathy (LENCEP; 620711), Kevelam et al. (2016) identified compound heterozygous missense mutations in the HMBS gene: R167Q and R225Q (609806.0047). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. At least 2 unaffected sibs carried a heterozygous R225Q variant. HMBS erythrocyte activity ranged from 55 to 67% of normal controls in the affected sibs, similar to heterozygous carriers of HMBS mutations. One unaffected sib had 83% activity and the other had 105% activity. Kevelam et al. (2016) noted that both the R225Q and R167Q mutations had been reported in the heterozygous state in patients with autosomal dominant AIP. </p><p>In a 45-year-old man (P3), born of unrelated Dutch parents (family 2), with LENCEP, Stutterd et al. (2021) identified compound heterozygosity for the R225Q and R167Q mutations. His mother, who was heterozygous for the R167Q mutation, had latent AIP; his father was unavailable for testing. A measurement of HMBS enzyme activity was not available for P3. Stutterd et al. (2021) noted that the pathogenicity of the R225Q variant had not been conclusively demonstrated and that previous functional studies had yielded conflicting results of the effect of this variant on HMBS enzyme activity. Stutterd et al. (2021) also identified a homozygous missense mutation in the HMBS gene (A84D; 609806.0048) in 2 adult sibs, born of consanguineous Lebanese parents (family 1), with slowly progressive LENCEP. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not present in the gnomAD database. Erythrocyte HMBS enzyme activity in the affected sibs ranged from 13 to 18% of normal control values. Erythrocyte HMBS activity in an unaffected sib who was heterozygous for the mutation was 50% of normal. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
|
|
<p>During study of the pathogenesis of the neurologic symptoms of AIP, Lindberg et al. (1996) generated Pbgd-deficient mice by gene targeting. These mice exhibited typical biochemical characteristics of human AIP, including decreased hepatic Pbgd activity, increased delta-aminolevulinic acid synthase (ALAS1; 125290) activity, and massively increased urinary excretion of the heme precursor delta-aminolevulinic acid after treatment with drugs such as phenobarbital. Behavioral tests revealed decreased motor function and histopathologic findings, including axonal neuropathy and neurologic muscle atrophy. </p><p>Homedan et al. (2015) studied the AIP mouse model generated by Lindberg et al. (1996), in which the mice were compound heterozygous for a null Hmbs allele and a functional Hmbs allele with a mild mutation. They had previously found that Hmbs mutant liver showed deficiencies in mitochondrial complexes I through III. Homedan et al. (2015) found tissue-specific alterations in mitochondrial complexes in Hmbs mutant brain and muscle in the basal state. Phenobarbital-induced AIP was accompanied by a sharp alteration of oxidative metabolism in muscle, with significantly decreased ATP production in Hmbs mutant skeletal muscle due to deficiencies in complexes I and II. In contrast, all 4 respiratory chain complexes were affected in Hmbs mutant brain. </p><p>Clavero et al. (2010) described a naturally occurring feline model of AIP in 4 unrelated cat lines that presented phenotypically as congenital erythropoietic porphyria (CEP; 263700). Affected cats had erythrodontia, brownish urine, fluorescent bones, and markedly elevated urinary uroporphyrin and coproporphyrin, consistent with CEP. However, their UROS activities (deficient in CEP) were normal. Notably, affected cats had half-normal HMBS activities and elevated urinary 5-aminolevulinic acid (5-ALA) and PBG. Sequencing the feline Hmbs gene revealed different mutations in each line, including a duplication, an in-frame 3-bp deletion (842delGAG), and 2 missense (A84T and R149W) mutations. The 842delGAG and R149W mutations were identical to mutations reported in human. Prokaryotic expression of the 842delGAG and R149W mutations resulted in mutant enzymes with less than 1% wildtype activity, whereas the A84T mutation expressed a stable enzyme with approximately 35% of wildtype activity. The discolored teeth from the affected cats contained markedly elevated URO I and III, accounting for the CEP-like phenocopy. In 3 lines, the phenotype was an autosomal dominant trait, while affected cats with the A84T mutation were homozygous, a unique recessive form of AIP. </p><p>Yasuda et al. (2019) developed 2 separate mouse models with compound heterozygous missense mutations in the Hmbs gene: R167Q (609806.0005) and R173Q (609806.0006). Homozygosity for the R173Q mutation resulted in 1% of normal Hmbs activity and was embryonic lethal, whereas homozygosity for the R167Q mutation resulted in approximately 5% of normal Hmbs activity. Homozygous R167Q mice had elevated plasma and urinary 5-ALA and PBG at baseline, thought to be due to local production rather than transport through the blood brain barrier, and phenotypic features of delayed eye opening, severe early-onset ataxia, delayed motor development, and abnormal rotarod performance at 2 to 3 months of age, which progressively worsened. Brain myelination was delayed and total myelin volume was decreased by approximately 30% compared to wildtype littermates. In comparison to the T1/T2 mouse model of AIP, which has approximately 30% residual Hmbs activity, heme concentrations in liver and brain were similar, whereas 5-ALA and PBG concentrations were elevated in brain and CSF in R167Q mice. This suggests that the 5-ALA and PBG underlie the neurologic phenotype as opposed to reduced heme. Porphyrinogenic stimuli, including fasting and phenobarbital administration, led to no or mild changes in Alas1 mRNA levels and 5-ALA and PBG levels. R167Q homozygous mice had grossly normal brain and spinal cord at age 12 months and normal femoral nerve structures at age 6 months. (In the article by Yasuda et al. (2019), the mutations were also stated as Arg167Glu and Arg173Glu, which would be R167E and R173E, respectively. Yasuda (2020) confirmed that the mutations are Arg167Gln (R167Q) and Arg173Gln (R173Q).) </p><p>Berger et al. (2020) found that mice homozygous for the R167Q mutation in the Hmbs gene (609806.0005) showed depression-like behavioral abnormalities. RNA-seq analysis of hippocampal tissue from mutant mice showed differentially expressed genes (DEGs) compared to controls. The DEGs were involved in myelination in the CNS and oligodendrocyte development. Mutant mice had fewer hippocampal oligodendrocytes compared to controls and there was evidence of disrupted mitochondrial energy metabolism. Hippocampal neurons in mutant mice showed impaired neuronal cell proliferation and differentiation and aberrant synaptic plasticity. The findings implicated defective myelination as the pathogenic mechanism in the behavioral and neuronal plasticity defects and suggested that mitochondrial dysfunction may play a role. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
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</span>
|
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<strong>48 Selected Examples):</strong>
|
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</span>
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</h4>
|
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<div>
|
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<p />
|
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0001 PORPHYRIA, ACUTE INTERMITTENT, NONERYTHROID VARIANT</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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HMBS, IVS1DS, G-A, +1
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<br />
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|
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SNP: rs1565750784,
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|
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ClinVar: RCV000001506, RCV002512650
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In affected members of a large Dutch family with the nonerythroid variant of acute intermittent porphyria (AIP; 176000), Grandchamp et al. (1989) identified a heterozygous G-to-A transition in the 5-prime splice donor site of intron 1 of the HMBS gene. The mutation interrupted the sequence coding for the nonerythroid isoform of PBGD; thus, expression of the erythroid isoform was unaffected. Hybridization analysis using oligonucleotide probes after in vitro amplification of genomic DNA offered another possibility of detecting asymptomatic carriers of the mutation in affected families. </p><p>Puy et al. (1997, 1998) identified this splice site mutation in patients with nonerythroid variant AIP. </p><p>Petrides (1998) identified the G-to-A transition in intron 1 of the HMBS gene in 9 members of a German kindred in which the proband had a life-threatening coma due to the nonerythroid variant of AIP. The newly identified family members were taught how to prevent porphyric attacks. </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 PORPHYRIA, ACUTE INTERMITTENT</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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HMBS, EX12DEL
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<br />
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|
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SNP: rs1555206170,
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|
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ClinVar: RCV000578508, RCV002255098
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a patient with acute intermittent porphyria (AIP; 176000), Grandchamp et al. (1989) identified a heterozygous G-to-A transition in exon 12 of the HMBS gene, resulting in the skipping of exon 12. The resulting aberrant mRNA encoded a truncated protein that was inactive, but stable, and could be detected using antibodies directed against the normal enzyme (CRM-positive). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0003 PORPHYRIA, ACUTE INTERMITTENT, NONERYTHROID VARIANT</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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HMBS, IVS1DS, G-T, +1
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<br />
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SNP: rs1565750784,
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ClinVar: RCV000001509, RCV002512651
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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 Finnish family with the nonerythroid variant of acute intermittent porphyria (AIP; 176000) Grandchamp et al. (1989) identified a G-to-T transversion in the 5-prime splice donor sequence of intron 1 of the HMBS gene. This is only 1 nucleotide removed from the mutation listed as 609806.0001, in which the change occurred in the first nucleotide of intron 1. Grandchamp et al. (1989) proposed that both of these mutations resulted in an abnormal splicing of primary transcripts initiated at the upstream promoter of the gene without affecting the expression of the PBGD gene in erythroid cells where the downstream promoter is utilized. A similar mutation located at the last position of exon 1 of the beta-globin gene was found by Vidaud et al. (1989) to be responsible for a splicing defect leading to beta-thalassemia. </p>
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</span>
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</div>
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<div>
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<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, ARG116TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs118204094,
|
|
|
|
|
|
gnomAD: rs118204094,
|
|
|
|
|
|
ClinVar: RCV000001510, RCV001212053
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a Swedish family with acute intermittent porphyria (AIP; 176000), Lee et al. (1990) identified a C-to-T transition in exon 8 of the HMBS gene, resulting in an arg116-to-trp (R116W) substitution.</p><p>The R116W mutation was found by Gu et al. (1993) in 15 Dutch AIP families and in 1 French AIP family. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
ENCEPHALOPATHY, PORPHYRIA-RELATED, INCLUDED<br />
|
|
LEUKOENCEPHALOPATHY, PORPHYRIA-RELATED, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, ARG167GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs118204095,
|
|
|
|
|
|
gnomAD: rs118204095,
|
|
|
|
|
|
ClinVar: RCV000001511, RCV000520560, RCV003764509, RCV003764510
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Acute Intermittent Porphyria</em></strong></p><p>
|
|
In patients with acute intermittent porphyria (AIP; 176000), Delfau et al. (1990) identified a heterozygous G-to-A transition in exon 10 of the HMBS gene, resulting in an arg167-to-gln (R167Q) substitution. </p><p><strong><em>Porphyria-Related Encephalopathy</em></strong></p><p>
|
|
In a Dutch girl with porphyria-related encephalopathy (ENCEP; 620704) originally reported by Beukeveld et al. (1990), Picat et al. (1990) identified compound heterozygous missense mutations in the HMBS gene: R167Q and R173Q (609806.0006). The parents, who had classic AIP, were each heterozygous for 1 of the mutations. </p><p>In an English brother and sister with ENCEP, Llewellyn et al. (1992) identified compound heterozygosity for 2 mutations in the HMBS gene: a c.500G-A transition, resulting in an R167Q substitution, and a c.499C-T transition, resulting in an R167W substitution (609806.0013). Erythrocyte HMBS activity ranged from 14 to 17% of controls. Each clinically unaffected parent was heterozygous for 1 of the variants and had about a 50% reduction in HMBS activity. </p><p><strong><em>Porphyria-Related Leukoencephalopathy</em></strong></p><p>
|
|
For discussion of the R167Q mutation (c.500G-A, NM_000190.3) in the HMBS gene that was found in compound heterozygous state with R225Q (609806.0047) in 2 Dutch families with porphyria-related leukoencephalopathy (LENCEP; 620711) by Kevelam et al. (2016) and Stutterd et al. (2021), see 609806.0047. </p><p><strong><em>Variant Function</em></strong></p><p>
|
|
In in vitro studies, Solis et al. (2004) found that the R167Q variant had about 1% residual HMBS activity. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
ENCEPHALOPATHY, PORPHYRIA-RELATED, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, ARG173GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs118204096,
|
|
|
|
|
|
|
|
ClinVar: RCV000001512, RCV001851550, RCV003764511
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Acute Intermittent Porphyria</em></strong></p><p>
|
|
In patients with acute intermittent porphyria (AIP; 176000), Delfau et al. (1990) identified a heterozygous G-to-A transition in exon 10 of the HMBS gene, resulting in an arg173-to-gln (R173Q) substitution. </p><p>Kauppinen et al. (1992) identified the R173Q substitution in 3 out of 7 Finnish families with CRM-positive AIP. </p><p><strong><em>Porphyria-Related Encephalopathy</em></strong></p><p>
|
|
In a Dutch patient with porphyria-related encephalopathy (ENCEP; 620704) originally reported by Beukeveld et al. (1990), Picat et al. (1990) identified compound heterozygous missense mutations in the HMBS gene: R173Q and R167Q (609806.0005). The parents, who had symptomatic AIP (the mother) or latent AIP (the father), were each heterozygous for 1 of the mutations and had about 50% decreased erythrocyte HMBS activity. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, GLN155TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs118204097,
|
|
|
|
|
|
|
|
ClinVar: RCV000001513
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 1 of 43 unrelated patients with acute intermittent porphyria (AIP; 176000), Scobie et al. (1990) identified a C-to-T transition in the HMBS gene, resulting in a gln155-to-ter (Q155X) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, ARG149GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs118204098,
|
|
|
|
|
|
|
|
ClinVar: RCV000001514
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with acute intermittent porphyria (AIP; 176000), Delfau et al. (1991) identified a c.446G-A transition in exon 9 of the HMBS gene, resulting in an arg149-to-gln (R159Q) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, LEU245ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs118204099,
|
|
|
|
|
|
|
|
ClinVar: RCV000001515
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with acute intermittent porphyria (AIP; 176000), Delfau et al. (1991) identified a c.734T-G transversion in exon 12 of the HMBS gene, resulting in a leu245-to-arg (L245R) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, 1-BP DEL, 900T
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1565758825,
|
|
|
|
|
|
|
|
ClinVar: RCV000001516
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with CRM-positive acute intermittent porphyria (AIP; 176000), Delfau et al. (1991) identified a 1-bp deletion (c.900delT) in exon 1 of the HMBS gene, resulting in a stop codon located 15 codons downstream from the deletion. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, 9-BP DEL, EX10
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1592217847,
|
|
|
|
|
|
|
|
ClinVar: RCV000807846, RCV002249519
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with CRM-positive acute intermittent porphyria (AIP; 176000), Delfau et al. (1991) identified a deletion of the last 9 bp of exon 10. This resulted from abnormal splicing of intron 10 which was a consequence of a G-to-T substitution of the last base of exon 10. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, TRP198TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs118204100,
|
|
|
|
|
|
|
|
ClinVar: RCV000001518
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a northern Swedish (Lappland) family with acute intermittent porphyria (AIP; 176000), Lee and Anvret (1991) identified a G-to-A transition in exon 10 of the HMBS gene, resulting in a trp198-to-ter (W198X) substitution. The same mutation was found in 15 of 33 Swedish AIP families. Genealogic data showed that 12 of the 15 were related, indicating a founder effect. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
ENCEPHALOPATHY, PORPHYRIA-RELATED, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, ARG167TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs118204101,
|
|
|
|
|
|
gnomAD: rs118204101,
|
|
|
|
|
|
ClinVar: RCV000001521, RCV000489906, RCV003764512
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Acute Intermittent Porphyria</em></strong></p><p>
|
|
The seemingly high frequency of mutations in exon 10 of the PBGD gene (Delfau et al., 1990) prompted Gu et al. (1992) to screen this exon in 41 unrelated patients with autosomal dominant AIP (AIP; 176000) by use of denaturing gradient gel electrophoresis (DGGE) after PCR amplification. In about one-fourth of the patients, they distinguished 3 abnormal migration patterns, indicating the presence of mutation in heterozygous state. Sequencing demonstrated the presence of 3 different single-base substitutions: R167Q (609806.0005), R173Q (609806.0006), and R167W. </p><p>In Finland, Kauppinen et al. (1992) found an R167W mutation in 3 out of 7 families with CRM-positive AIP. DNA analyses of family members demonstrated that conventional assays of erythrocyte PBGD activity identified correctly only 72% of the carriers of the mutation. </p><p><strong><em>Porphyria-Related Encephalopathy</em></strong></p><p>
|
|
In an English brother and sister with porphyria-related encephalopathy (ENCEP; 620704), Llewellyn et al. (1992) identified compound heterozygosity for 2 mutations in the PBGD gene: a c.499C-T transition, resulting in an arg167-to-trp (R167W) substitution, and an adjacent c.500G-A transition, resulting in an R167Q (609806.0005) substitution. Erythrocyte HMBS activity was 14 to 17% of normal controls. </p><p>Solis et al. (2004) reported a Spanish patient with ENCEP who was homozygous for the R167W substitution. Both parents were heterozygous for the mutation. The patient had 1% residual HMBS activity. The clinically asymptomatic parents were heterozygous for the mutation and had about 50% HMBS activity. The proband had a severe disease course with psychomotor delay, dystonic movements, axial hypotonia, delayed myelination, and death at age 40 months. </p><p><strong><em>Variant Function</em></strong></p><p>
|
|
Solis et al. (2004) noted that the R167W, R173Q, and R167Q mutations all occur at CpG dinucleotides within exon 10, and can thus be considered mutation hotspots. All 3 substitutions alter highly conserved arginines in the enzyme's active site, which interact with the precursor porphobilinogen and the acidic side chains of the enzyme's dipyrromethane cofactor. Functional expression studies showed that all 3 substitutions resulted in less than 2% normal HMBS activity. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, ARG167LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs118204095,
|
|
|
|
|
|
gnomAD: rs118204095,
|
|
|
|
|
|
ClinVar: RCV000001522
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Using site-directed mutagenesis, Lander et al. (1991) demonstrated that an arg167-to-leu (R167L) substitution in the HMBS protein resulted in a profound decrease of PBGD activity, consistent with acute intermittent porphyria (AIP; 176000). It is noteworthy that substitution of arg167 by glutamine (R167Q; 609806.0005) and by tryptophan (R167W; 609806.0013) resulted in loss of enzyme activity. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, ARG26HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs118204103,
|
|
|
|
|
|
|
|
ClinVar: RCV000001508, RCV000798844
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with CRM-positive acute intermittent porphyria (AIP; 176000), Llewellyn et al. (1993) identified a c.77G-A transition in exon 3 of the HMBS gene, resulting in an arg26-to-his (R26H) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, ALA31THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs118204104,
|
|
|
|
|
|
|
|
ClinVar: RCV000001519
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with CRM-positive acute intermittent porphyria (AIP; 176000), Gu et al. (1994) identified a c.91G-A transition in exon 4 of the HMBS gene, leading to an ala31-to-thr (A31T) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, GLN34LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs118204105,
|
|
|
|
|
|
|
|
ClinVar: RCV000001520
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with CRM-negative acute intermittent porphyria (AIP; 176000), Mgone et al. (1992) identified a c.100C-A transversion in exon 4 of the HMBS gene, resulting in a gln34-to-lys (Q34K) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, ALA55SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs118204106,
|
|
|
|
|
|
|
|
ClinVar: RCV000001523, RCV002272005, RCV003234886
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with CRM-positive acute intermittent porphyria (AIP; 176000), Gu et al. (1994) identified a c.163G-T transversion in exon 5 of the HMBS gene, resulting in an ala55-to-ser (A55S) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, 1-BP DEL, 174C
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1565754285,
|
|
|
|
|
|
|
|
ClinVar: RCV000001524
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with CRM-negative acute intermittent porphyria (AIP; 176000), Gu et al. (1994) identified a 1-bp deletion (c.174delC) in exon 5 of the HMBS gene. This frameshift mutation leads to a premature termination 40 codons downstream and a truncated protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, 1-BP INS, 182G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1565754296,
|
|
|
|
|
|
|
|
ClinVar: RCV000001525
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with CRM-negative acute intermittent porphyria (AIP; 176000), Gu et al. (1994) identified a 1-bp insertion (c.182insG) in exon 5 of the HMBS gene. This frameshift mutation leads to a premature termination 5 codons downstream and a truncated protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, IVS5DS, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1565754452,
|
|
|
|
|
|
|
|
ClinVar: RCV000001526
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with CRM-negative acute intermittent porphyria (AIP; 176000), Gu et al. (1994) identified a c.210G-A substitution in the first nucleotide of the donor splice site of intron 5 of the HMBS gene, resulting in abnormal splicing. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, 2-BP DEL, 218AG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1592214498,
|
|
|
|
|
|
|
|
ClinVar: RCV000809200, RCV002280823
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with CRM-negative acute intermittent porphyria (AIP; 176000), Gu et al. (1994) identified a 2-bp deletion (c.218delAG) in exon 6 of the HMBS gene. This frameshift mutation leads to a premature termination 9 codons downstream and a truncated protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, GLY111ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs118204107,
|
|
|
|
|
|
|
|
ClinVar: RCV000001529, RCV001381874
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with CRM-negative acute intermittent porphyria (AIP; 176000), Gu et al. (1994) identified a c.331G-A transition in exon 7 of the HMBS gene, resulting in a gly111-to-arg (G111R) substitution. </p><p>In Argentina, De Siervi et al. (1999) found that the G111R mutation was present in 12 of 26 (46%) presumably unrelated propositi with AIP; haplotype analysis with intragenic and flanking markers indicated an ancestral founder. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0024 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, IVS9AS, G-A, -1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1565756481,
|
|
|
|
|
|
|
|
ClinVar: RCV000001530, RCV001389654
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with acute intermittent porphyria (AIP; 176000), Lundin et al. (1994) identified a c.499G-A transition in the first nucleotide of the acceptor splice site of intron 9 of the HMBS gene, resulting in abnormal splicing. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0025 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, LEU177ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs118204108,
|
|
|
|
|
|
|
|
ClinVar: RCV000001531, RCV000795368
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of several unrelated Finnish and Dutch families with acute intermittent porphyria (AIP; 176000), Mgone et al. (1992) identified a c.530T-G transversion in exon 10 of the HMBS gene, resulting in a leu177-to-arg (L177R) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0026 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, ARG201TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs118204109,
|
|
|
|
|
|
gnomAD: rs118204109,
|
|
|
|
|
|
ClinVar: RCV000001527, RCV000432186, RCV004584591
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with acute intermittent porphyria (AIP; 176000), Lundin et al. (1994) identified a c.601C-T transition in exon 10 of the HMBS gene, resulting in an arg201-to-trp (R201W) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0027 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, GLU223LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs118204110,
|
|
|
|
|
|
|
|
ClinVar: RCV000001532, RCV001209137
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with CRM-negative acute intermittent porphyria (AIP; 176000), Gu et al. (1994) identified a c.667G-A transition in exon 12 of the HMBS gene, resulting in a glu223-to-lys (E223K) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0028 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, 2-BP DEL, 730CT
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1565757839,
|
|
|
|
|
|
|
|
ClinVar: RCV000001533, RCV001389655
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with CRM-negative acute intermittent porphyria (AIP; 176000), Mgone et al. (1993) and Gu et al. (1994) identified a 2-bp deletion (c.730delCT) exon 12 of the HMBS gene. This frameshift mutation leads to a premature termination 6 codons downstream and a truncated protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0029 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, CYS247ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs118204111,
|
|
|
|
|
|
|
|
ClinVar: RCV000001534, RCV002298429
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with acute intermittent porphyria (AIP; 176000), Mgone et al. (1993) identified a c.739T-C transition in exon 12 of the HMBS gene, resulting in a cys247-to-arg (C247R) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0030 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, 8-BP INS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1565757857,
|
|
|
|
|
|
|
|
ClinVar: RCV000001535
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with CRM-negative acute intermittent porphyria (AIP; 176000), Gu et al. (1994) identified an 8-bp insertion at position c.742 of the coding sequence in exon 12 of the HMBS gene. This frameshift mutation leads to a premature termination 10 codons downstream and a truncated protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0031 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, GLU250LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs118204112,
|
|
|
|
|
|
|
|
ClinVar: RCV000001536
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with CRM-negative acute intermittent porphyria (AIP; 176000), Gu et al. (1994) identified a c.748G-A transition in exon 12 of the HMBS gene, resulting in a glu250-to-lys (E250K) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0032 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, ALA252THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs118204113,
|
|
|
|
|
|
gnomAD: rs118204113,
|
|
|
|
|
|
ClinVar: RCV000001537, RCV002512652
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with acute intermittent porphyria (AIP; 176000), Mgone et al. (1993) identified a c.754G-A transition in exon 12 of the HMBS gene, resulting in an ala252-to-thr (A252T) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0033 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, ALA252VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs118204114,
|
|
|
|
|
|
gnomAD: rs118204114,
|
|
|
|
|
|
ClinVar: RCV000001538
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with acute intermittent porphyria (AIP; 176000), Mgone et al. (1993) identified a c.755C-T transition in exon 12 of the HMBS gene, resulting in an ala252-to-val (A252V) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0034 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, HIS256ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs118204115,
|
|
|
|
|
|
|
|
ClinVar: RCV000001539
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with acute intermittent porphyria (AIP; 176000), Mgone et al. (1993) identified a c.766C-A transversion in exon 12 of the HMBS gene, resulting in a his256-to-asn (H256N) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0035 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, IVS12DS, G-C, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1565758008,
|
|
|
|
|
|
|
|
ClinVar: RCV000001540
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese patient with acute intermittent porphyria (AIP; 176000), Daimon et al. (1993) identified a c.771G-C transversion in the first nucleotide of the donor site of intron 12 of the HMBS gene, resulting in aberrant splicing and the skipping of exon 12. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0036 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, IVS14DS, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1946325053,
|
|
|
|
|
|
|
|
ClinVar: RCV000001541, RCV001851551
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with CRM-negative acute intermittent porphyria (AIP; 176000), Gu et al. (1993) identified a c.912G-A transition in the first nucleotide of the donor splice site of intron 14 of the HMBS gene, resulting in abnormal splicing and the skipping of exon 14. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0037 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, IVS6DS, G-C, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1565754565,
|
|
|
|
|
|
|
|
ClinVar: RCV000001542
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of 28 Swedish families with CRM-negative acute intermittent porphyria (AIP; 176000), Lundin et al. (1997) identified a G-to-C transversion at the splice donor site of intron 6 of the HMBS gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0038 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, GLY216ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs118204116,
|
|
|
|
|
|
|
|
ClinVar: RCV000001543, RCV001851552
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a Swedish family with CRM-negative acute intermittent porphyria (AIP; 176000), Lundin et al. (1997) identified a c.646G-A transition in exon 11 of the HMBS gene, resulting in a gly216-to-asp (G216D) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0039 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, 2-BP DEL, 847TG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1592220835,
|
|
|
|
|
|
|
|
ClinVar: RCV000001544
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a Swedish family with acute intermittent porphyria (AIP; 176000), Lundin et al. (1997) identified a 2-bp deletion (c.847delTG) in exon 14 of the HMBS gene, resulting in an mRNA translational frameshift. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0040 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, ALU INS
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000001545
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Mustajoki et al. (1999) reported a large Finnish family in which an Alu element interfered with the coding region of the PBGD gene, resulting in acute intermittent porphyria (AIP; 176000). A 333-bp Alu sequence was directly inserted into exon 5 in antisense orientation. Mustajoki et al. (1999) noted that this Alu cassette belongs to a Ya5 subfamily, one of the evolutionarily youngest and at that time most active Alu subfamilies. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0041 PORPHYRIA, ACUTE INTERMITTENT, NONERYTHROID VARIANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, 1-BP DEL, -154G, PROMOTER
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000001546
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Whatley et al. (2000) identified a 1-bp deletion (-154delG) in the promoter region of the HMBS gene as the cause of the nonerythroid variant of acute intermittent porphyria (AIP; 176000). Reporter gene and electromobility shift assays showed that the G nucleotide at position -154, the most 5-prime of several transcription initiation sites in the ubiquitous HMBS promoter, which lies immediately 3-prime to a transcription factor IIB binding motif, is essential for normal transcription. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0042 PORPHYRIA, ACUTE INTERMITTENT, NONERYTHROID VARIANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, 1-BP DEL, 41A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1592212904,
|
|
|
|
|
|
|
|
ClinVar: RCV000001547
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Whatley et al. (2000) identified a 1-bp deletion (c.41delA) in exon 3 of the HMBS gene as the cause of the nonerythroid variant of acute intermittent porphyria (AIP; 176000). The frameshift mutation introduced a stop codon into mRNA for the ubiquitous isoform only. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0043 PORPHYRIA, ACUTE INTERMITTENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, TRP283TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs118204117,
|
|
|
|
|
|
gnomAD: rs118204117,
|
|
|
|
|
|
ClinVar: RCV000001548, RCV000418446
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with acute intermittent porphyria (AIP; 176000), Chen et al. (1994) identified a heterozygous c.848G-A transition in exon 14 of the HMBS gene, resulting in a trp283-to-ter (W283X) substitution. </p><p>Nearly 60% of all Swiss AIP patients carry the W283X mutation. In France, the prevalence of W283X is less than 5% (Schneider-Yin et al., 2002). In 12 of 25 AIP families of Swiss and French origin, Schneider-Yin et al. (2002) identified a common haplotype containing the W283X HMBS mutation. The authors suggested that a single mutational event took place approximately 40 generations ago (i.e., 1,000 years ago). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0044 PORPHYRIA, ACUTE INTERMITTENT, NONERYTHROID VARIANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, MET1VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs118204118,
|
|
|
|
|
|
|
|
ClinVar: RCV000001549, RCV001851553
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with the nonerythroid variant of acute intermittent porphyria (AIP; 176000), Chen et al. (1994) identified a heterozygous c.3G-A transition in exon 1 of the HMBS gene, resulting in a met1-to-val (M1V) substitution in the initiation of translation codon for the housekeeping transcript. Thus, translation of the erythrocyte transcript was unaffected. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0045 ENCEPHALOPATHY, PORPHYRIA-RELATED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HMBS, LEU81PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs118204119,
|
|
|
|
|
|
|
|
ClinVar: RCV003764513
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 7-year-old boy, born of consanguineous Turkish parents, with porphyria-related encephalopathy (ENCEP; 620704), Hessels et al. (2004) identified a homozygous leu81-to-pro (L81P) substitution in exon 6 of the HMBS gene. Porphobilinogen activity in red cells was decreased to 2 to 4%. Both parents were heterozygous and asymptomatic. Leu81 in PBG deaminase is an evolutionarily conserved residue in the second alpha helix, suggesting its structural importance for preservation of enzyme activity. </p>
|
|
</span>
|
|
</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>.0046 PORPHYRIA, ACUTE INTERMITTENT</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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HMBS, ARG149TER
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<br />
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SNP: rs118204120,
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ClinVar: RCV000001551, RCV001389642, RCV003924793
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</span>
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</div>
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<span class="mim-text-font">
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<p>In affected members of 2 Finnish families with acute intermittent porphyria (AIP; 176000), Kauppinen et al. (1995) identified a heterozygous c.445C-T transition in exon 9 of the HMBS gene, resulting in an arg149-to-ter (R149X) substitution. </p><p>Poblete-Gutierrez et al. (2006) identified a heterozygous R149X substitution in affected members of the original family with so-called 'Chester type porphyria' (McColl et al., 1985) (see 176000). The mutation was not found in 200 control chromosomes. The family had originally been reported as having features of both AIP and variegated porphyria (VP; 176200), but no mutations in the PPOX gene (600923) were identified. The mutation occurred at a hypermutable CpG dinucleotide. The findings confirmed that Chester type porphyria is a variant of AIP. Poblete-Gutierrez et al. (2006) suggested that the original biochemical studies indicating PPOX deficiency may have been erroneous or misinterpreted. A different mutation in this codon has also been associated with AIP (R149Q; 609806.0008). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0047 LEUKOENCEPHALOPATHY, PORPHYRIA-RELATED</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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HMBS, ARG225GLN
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<br />
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SNP: rs142459647,
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gnomAD: rs142459647,
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ClinVar: RCV000148511, RCV000498317, RCV003764896
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</span>
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</div>
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<span class="mim-text-font">
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<p>In 3 adult sibs, born of unrelated Dutch parents, with slowly progressive porphyria-related leukoencephalopathy (LENCEP; 620711), Kevelam et al. (2016) identified compound heterozygous missense mutations in the HMBS gene: a c.674G-A transition in exon 12, resulting in an arg225-to-gln (R225Q) substitution, and R167Q (609806.0005). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. HMBS erythrocyte activity ranged from 55 to 67% of normal controls in the affected sibs, similar to heterozygous carriers of HMBS mutations. At least 2 unaffected sibs carried a heterozygous R225Q variant; HMBS activity was 83% of controls in 1 and 105% of controls in the other. Urine and plasma PBG were mildly elevated (2- to 4-fold increase in urine) in the affected sibs, but not in the unaffected carrier sibs. Plasma ALA levels were borderline elevated in both affected and unaffected sibs. Kevelam et al. (2016) noted that both the R225Q and R167Q mutations had been reported in the heterozygous state in patients with autosomal dominant acute intermittent porphyria (AIP; 176000). The authors concluded that either the mildly reduced enzyme activity with mildly elevated ALA and PBG did not cause the chronic leukoencephalopathy observed in the 3 sibs with biallelic variants, or that the enzyme activity in erythrocytes does not reflect enzyme activity in the brain. </p><p>In a 45-year-old man (P3), born of unrelated Dutch parents (family 2), with LENCEP, Stutterd et al. (2021) identified compound heterozygosity for the R225Q (c.674G-A, NM_000190.3) and R167Q mutations. His mother, who was heterozygous for the R167Q mutation, had latent AIP; his father was unavailable for testing. A measurement of HMBS enzyme activity was not available for P3. Stutterd et al. (2021) noted that the pathogenicity of the R225Q variant has not been conclusively demonstrated and that previous functional studies have yielded conflicting results of the effect of this variant on HMBS enzyme 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>.0048 LEUKOENCEPHALOPATHY, PORPHYRIA-RELATED</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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HMBS, ALA84ASP
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<br />
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ClinVar: RCV003881685
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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 2 adult sibs, born of consanguineous Lebanese parents (family 1), with slowly progressive porphyria-related leukoencephalopathy (LENCEP; 620711), Stutterd et al. (2021) identified a homozygous c.251C-A transversion (c.251C-A, NM_000190.3) in the HMBS gene, resulting in an ala84-to-asp (A84D) substitution at a conserved residue in the second alpha-helix. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not present in the gnomAD database. Erythrocyte HMBS enzyme activity ranged from 13 to 18% of normal control values in the sibs. HMBS erythrocyte activity in an unaffected sib who was heterozygous for the mutation was 50% of normal. The patients had onset of progressive neurologic symptoms in the first decade. </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>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Llewellyn et al. (1987)
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Berger, S., Stattmann, M., Cicvaric, A., Monje, F. J., Coiro, P., Hotka, M., Ricken, G., Hainfellner, J., Greber-Platzer, S., Yasuda, M., Desnick, R. J., Pollak, D. D.
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|
<strong>Severe hydroxymethylbilane synthase deficiency causes depression-like behavior and mitochondrial dysfunction in a mouse model of homozygous dominant acute intermittent porphyria.</strong>
|
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Acta Neuropath. Commun. 8: 38, 2020.
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[PubMed: 32197664]
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[Full Text: https://doi.org/10.1186/s40478-020-00910-z]
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</p>
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<li>
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<p class="mim-text-font">
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Beukeveld, G. J. J., Wolthers, B. G., Nordmann, Y., Deybach, J. C., Grandchamp, B., Wadman, S. K.
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<strong>A retrospective study of a patient with homozygous form of acute intermittent porphyria.</strong>
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J. Inherit. Metab. Dis. 13: 673-683, 1990.
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[PubMed: 2246851]
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[Full Text: https://doi.org/10.1007/BF01799566]
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Chen, C. H., Astrin, K. H., Lee, G., Anderson, K. E., Desnick, R. J.
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|
<strong>Acute intermittent porphyria: identification and expression of exonic mutations in the hydroxymethylbilane synthase gene: an initiation codon missense mutation in the housekeeping transcript causes 'variant acute intermittent porphyria' with normal expression of the erythroid-specific enzyme.</strong>
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J. Clin. Invest. 94: 1927-1937, 1994.
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[PubMed: 7962538]
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[Full Text: https://doi.org/10.1172/JCI117543]
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<p class="mim-text-font">
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Chretien, S., Dubart, A., Beaupain, D., Raich, N., Grandchamp, B., Rosa, J., Goossens, M., Romeo, P.-H.
|
|
<strong>Alternative transcription and splicing of the human porphobilinogen deaminase gene result either in tissue-specific or in housekeeping expression.</strong>
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Proc. Nat. Acad. Sci. 85: 6-10, 1988.
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[PubMed: 3422427]
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[Full Text: https://doi.org/10.1073/pnas.85.1.6]
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<p class="mim-text-font">
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Clavero, S., Bishop, D. F., Haskins, M. E., Giger, U., Kauppinen, R., Desnick, R. J.
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<strong>Feline acute intermittent porphyria: a phenocopy masquerading as an erythropoietic porphyria due to dominant and recessive hydroxymethylbilane synthase mutations.</strong>
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Hum. Molec. Genet. 19: 584-596, 2010.
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[PubMed: 19934113]
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[Full Text: https://doi.org/10.1093/hmg/ddp525]
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<li>
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<p class="mim-text-font">
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Daimon, M., Yamatani, K., Igarashi, M., Fukase, N., Ogawa, A., Tominaga, M., Sasaki, H.
|
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<strong>Acute intermittent porphyria caused by a G to C mutation in exon 12 of the porphobilinogen deaminase gene that results in exon skipping.</strong>
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Hum. Genet. 92: 549-553, 1993.
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[PubMed: 8262514]
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[Full Text: https://doi.org/10.1007/BF00420937]
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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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De Siervi, A., Rossetti, M. V., Parera, V. E., Astrin, K. H., Aizencang, G. I., Glass, I. A., Batlle, A. M. del C., Desnick, R. J.
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<strong>Identification and characterization of hydroxymethylbilane synthase mutations causing acute intermittent porphyria: evidence for an ancestral founder of the common G111R mutation.</strong>
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Am. J. Med. Genet. 86: 366-375, 1999.
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[PubMed: 10494093]
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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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de Verneuil, H., Phung, N., Nordmann, Y., Allard, D., Leprince, F., Jerome, H., Aurias, A., Rethore, M. O.
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<strong>Assignment of human uroporphyrinogen I synthase locus to region 11qter by gene dosage effect.</strong>
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Hum. Genet. 60: 212-213, 1982.
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[PubMed: 6985467]
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[Full Text: https://doi.org/10.1007/BF00303004]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Delfau, M. H., Picat, C., De Rooij, F., Voortman, G., Deybach, J. C., Nordmann, Y., Grandchamp, B.
|
|
<strong>Molecular heterogeneity of acute intermittent porphyria: identification of four additional mutations resulting in the CRIM-negative subtype of the disease.</strong>
|
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Am. J. Hum. Genet. 49: 421-428, 1991.
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[PubMed: 1714233]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Delfau, M. H., Picat, C., de Rooij, F. W. M., Hamer, K., Bogard, M., Wilson, J. H. P., Deybach, J. C., Nordmann, Y., Grandchamp, B.
|
|
<strong>Two different point G to A mutations in exon 10 of the porphobilinogen deaminase gene are responsible for acute intermittent porphyria.</strong>
|
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J. Clin. Invest. 86: 1511-1516, 1990.
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[PubMed: 2243128]
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[Full Text: https://doi.org/10.1172/JCI114869]
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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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Floderus, Y., Shoolingin-Jordan, P. M., Harper, P.
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<strong>Acute intermittent porphyria in Sweden. Molecular, functional and clinical consequences of some new mutations found in the porphobilinogen deaminase gene.</strong>
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Clin. Genet. 62: 288-297, 2002.
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[PubMed: 12372055]
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[Full Text: https://doi.org/10.1034/j.1399-0004.2002.620406.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">
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Grandchamp, B., de Verneuil, H., Beaumont, C., Chretien, S., Walter, O., Nordmann, Y.
|
|
<strong>Tissue-specific expression of porphobilinogen deaminase: two isoenzymes from a single gene.</strong>
|
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Europ. J. Biochem. 162: 105-110, 1987.
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|
[PubMed: 3816774]
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[Full Text: https://doi.org/10.1111/j.1432-1033.1987.tb10548.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">
|
|
Grandchamp, B., Delfau, M. H., Picat, C., de Rooij, F. W. M., Nordmann, Y.
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<strong>Heterogeneity of the molecular defects in acute intermittent porphyria. (Abstract)</strong>
|
|
Am. J. Hum. Genet. 47 (suppl.): A156 only, 1990.
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Grandchamp, B., Picat, C., de Rooij, F., Beaumont, C., Wilson, P., Deybach, J. C., Nordmann, Y.
|
|
<strong>A point mutation G-to-A in exon 12 of the porphobilinogen deaminase gene results in exon skipping and is responsible for acute intermittent porphyria.</strong>
|
|
Nucleic Acids Res. 17: 6637-6649, 1989.
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|
|
[PubMed: 2789372]
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[Full Text: https://doi.org/10.1093/nar/17.16.6637]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Grandchamp, B., Picat, C., Kauppinen, R., Mignotte, V., Peltonen, L., Mustajoki, P., Romeo, P. H., Goossens, M., Nordmann, Y.
|
|
<strong>Molecular analysis of acute intermittent porphyria in a Finnish family with normal erythrocyte porphobilinogen deaminase.</strong>
|
|
Europ. J. Clin. Invest. 19: 415-418, 1989.
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|
|
[PubMed: 2511016]
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[Full Text: https://doi.org/10.1111/j.1365-2362.1989.tb00252.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">
|
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Grandchamp, B., Picat, C., Mignotte, V., Wilson, J. H. P., te Velde, K., Sandkuyl, L., Romeo, P. H., Goossens, M., Nordmann, Y.
|
|
<strong>Tissue-specific splicing mutation in acute intermittent porphyria.</strong>
|
|
Proc. Nat. Acad. Sci. 86: 661-664, 1989.
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|
[PubMed: 2563167]
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[Full Text: https://doi.org/10.1073/pnas.86.2.661]
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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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Gu, X.-F., de Rooij, F., Lee, J. S., te Velde, K., Deybach, J.-C., Nordmann, Y., Grandchamp, B.
|
|
<strong>High prevalence of a point mutation in the porphobilinogen deaminase gene in Dutch patients with acute intermittent porphyria.</strong>
|
|
Hum. Genet. 91: 128-130, 1993.
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|
|
[PubMed: 8096492]
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[Full Text: https://doi.org/10.1007/BF00222712]
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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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Gu, X.-F., de Rooij, F., Voortman, G., te Velde, K., Deybach, J. C., Nordmann, Y., Grandchamp, B.
|
|
<strong>Detection of eleven mutations causing acute intermittent porphyria using denaturing gradient gel electrophoresis.</strong>
|
|
Hum. Genet. 93: 47-52, 1994.
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|
|
[PubMed: 8270254]
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[Full Text: https://doi.org/10.1007/BF00218912]
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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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Gu, X.-F., de Rooij, F., Voortman, G., te Velde, K., Nordmann, Y., Grandchamp, B.
|
|
<strong>High frequency of mutations in exon 10 of the porphobilinogen deaminase gene in patients with a CRIM-positive subtype of acute intermittent porphyria.</strong>
|
|
Am. J. Hum. Genet. 51: 660-665, 1992.
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[PubMed: 1496994]
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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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Gubin, A. N., Miller, J. L.
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<strong>Human erythroid porphobilinogen deaminase exists in 2 splice variants.</strong>
|
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Blood 97: 815-817, 2001.
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|
[PubMed: 11157504]
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[Full Text: https://doi.org/10.1182/blood.v97.3.815]
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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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Hessels, J., Voortman, G., van der Wagen, A., van der Elzen, C., Scheffer, H., Zuijderhoudt, F. M. J.
|
|
<strong>Homozygous acute intermittent porphyria in a 7-year-old boy with massive excretions of porphyrins and porphyrin precursors.</strong>
|
|
J. Inherit. Metab. Dis. 27: 19-27, 2004.
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[PubMed: 14970743]
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[Full Text: https://doi.org/10.1023/B:BOLI.0000016613.75677.05]
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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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Yasuda, M., Gan, L., Chen, B., Yu, C., Zhang, J., Gama-Sosa, M. A., Pollak, D. D., Berger, S., Phillips, J. D., Edelmann, W., Desnick, R. J.
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Yasuda, M.
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<strong>Personal Communication.</strong>
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