4101 lines
306 KiB
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4101 lines
306 KiB
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Entry
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- *607474 - HOMOGENTISATE 1,2-DIOXYGENASE; HGD
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- OMIM
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<p>
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<span class="h4">*607474</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="#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/607474">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div id="mimFloatingLinksMenu">
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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=ENSG00000113924;t=ENST00000283871" 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=3081" 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=607474" 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=ENSG00000113924;t=ENST00000283871" 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_000187,XM_005247412,XM_005247413,XM_005247414,XM_011512746,XM_017006277,XM_047448058,XM_047448059" 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_000187" 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=607474" 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=06315&isoform_id=06315_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/HGD" 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/1561616,1616743,2130647,2865609,18088530,47939115,115527117,119599928,119599929,119599930,158255000,189069305,193784873,296434531,530374528,530374530,530374532,767926537,1034632941,2217343678,2217343681,2462589542,2462589544,2462589546,2462589548,2462589550,2462589552,2462589554" 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/Q93099" 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=3081" 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=ENSG00000113924;t=ENST00000283871" 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=HGD" 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=HGD" 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+3081" 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/HGD" 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:3081" 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/3081" 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=chr3&hgg_gene=ENST00000283871.10&hgg_start=120628172&hgg_end=120682239&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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:4892" 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/hgd" 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=607474[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=607474[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/ENSG00000113924" 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=HGD" 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=HGD" 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=HGD" 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="http://www.alkaptonuria.cib.csic.es/index.htm" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=HGD&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/PA29268" 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:4892" 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/FBgn0040211.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:96078" 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/HGD#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:96078" 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/3081/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/OMIA001243/" 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=3081" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00001843;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-020802-5" 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:3081" 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=HGD&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> 360378009<br />
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<strong>ICD10CM:</strong> E70.29<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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607474
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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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HOMOGENTISATE 1,2-DIOXYGENASE; HGD
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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HOMOGENTISIC ACID OXIDASE; HGO
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=HGD" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">HGD</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/3/585?start=-3&limit=10&highlight=585">3q13.33</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:120628172-120682239&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'})">3:120,628,172-120,682,239</a> </span>
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</em>
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
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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>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/3/585?start=-3&limit=10&highlight=585">
|
|
3q13.33
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Alkaptonuria
|
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|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/203500"> 203500 </a>
|
|
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/607474" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/607474" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
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<p>The HGD gene encodes homogentisate 1,2-dioxygenase (HGD; <a href="https://enzyme.expasy.org/EC/1.13.11.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 1.13.11.5</a>), an enzyme involved in the catabolism of phenylalanine and tyrosine (summary by <a href="#16" class="mim-tip-reference" title="Vilboux, T., Kayser, M., Introne, W., Suwannarat, P., Bernardini, I., Fischer, R., O'Brien, K., Kleta, R., Huizing, M., Gahl, W. A. <strong>Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria.</strong> Hum. Mutat. 30: 1611-1619, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19862842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19862842</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19862842[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/10.1002/humu.21120" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19862842">Vilboux et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19862842" 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="#5" class="mim-tip-reference" title="Fernandez-Canon, J. M., Granadino, B., Beltran-Valero de Bernabe, D., Renedo, M., Fernandez-Ruiz, E., Penalva, M. A., Rodriguez de Cordoba, S. <strong>The molecular basis of alkaptonuria.</strong> Nature Genet. 14: 19-24, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782815</a>] [<a href="https://doi.org/10.1038/ng0996-19" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782815">Fernandez-Canon et al. (1996)</a> cloned the gene for homogentisate 1,2-dioxygenase. Characterization of the human HGD gene came from work with the ascomycete fungus Aspergillus nidulans in which a gene encoding an HGD enzyme, hmgA, had been cloned. The deduced amino acid sequence of its encoded protein product was used to identify EST clones putatively corresponding to the human HGD gene. HGD encodes a 445-amino acid polypeptide with high homology to the Aspergillus hmgA. By Northern blot analysis, <a href="#5" class="mim-tip-reference" title="Fernandez-Canon, J. M., Granadino, B., Beltran-Valero de Bernabe, D., Renedo, M., Fernandez-Ruiz, E., Penalva, M. A., Rodriguez de Cordoba, S. <strong>The molecular basis of alkaptonuria.</strong> Nature Genet. 14: 19-24, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782815</a>] [<a href="https://doi.org/10.1038/ng0996-19" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782815">Fernandez-Canon et al. (1996)</a> found highest expression of HGD in the prostate, small intestine, colon, and liver. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8782815" 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="#14" class="mim-tip-reference" title="Schmidt, S. R., Gehrig, A., Koehler, M. R., Schmid, M., Muller, C. R., Kress, W. <strong>Cloning of the homogentisate 1,2-dioxygenase gene, the key enzyme of alkaptonuria in mouse.</strong> Mammalian Genome 8: 168-171, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9069115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9069115</a>] [<a href="https://doi.org/10.1007/s003359900383" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9069115">Schmidt et al. (1997)</a> cloned the homogentisate 1,2-dioxygenase gene in the mouse. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9069115" 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="#5" class="mim-tip-reference" title="Fernandez-Canon, J. M., Granadino, B., Beltran-Valero de Bernabe, D., Renedo, M., Fernandez-Ruiz, E., Penalva, M. A., Rodriguez de Cordoba, S. <strong>The molecular basis of alkaptonuria.</strong> Nature Genet. 14: 19-24, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782815</a>] [<a href="https://doi.org/10.1038/ng0996-19" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782815">Fernandez-Canon et al. (1996)</a> determined that the HGD gene contains 14 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8782815" 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="#5" class="mim-tip-reference" title="Fernandez-Canon, J. M., Granadino, B., Beltran-Valero de Bernabe, D., Renedo, M., Fernandez-Ruiz, E., Penalva, M. A., Rodriguez de Cordoba, S. <strong>The molecular basis of alkaptonuria.</strong> Nature Genet. 14: 19-24, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782815</a>] [<a href="https://doi.org/10.1038/ng0996-19" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782815">Fernandez-Canon et al. (1996)</a> mapped the HGD gene to chromosome 3q21-q23 by a preliminary PCR screen of hamster/human somatic cell hybrid genomic DNA samples and by fluorescence in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8782815" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Gross, M. B. <strong>Personal Communication.</strong> Baltimore, Md. 4/25/2014."None>Gross (2014)</a> mapped the HGD gene to chromosome 3q13.33 based on an alignment of the HGD sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AF000573" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AF000573</a>) with the genomic sequence (GRCh37).</p>
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<p>In patients with alkaptonuria (AKU; <a href="/entry/203500">203500</a>), <a href="#5" class="mim-tip-reference" title="Fernandez-Canon, J. M., Granadino, B., Beltran-Valero de Bernabe, D., Renedo, M., Fernandez-Ruiz, E., Penalva, M. A., Rodriguez de Cordoba, S. <strong>The molecular basis of alkaptonuria.</strong> Nature Genet. 14: 19-24, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782815</a>] [<a href="https://doi.org/10.1038/ng0996-19" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782815">Fernandez-Canon et al. (1996)</a> identified missense mutations in the HGD gene that cosegregated with the disease (<a href="#0001">607474.0001</a>, <a href="#0002">607474.0002</a>), and provided biochemical evidence that at least one of these missense mutations is a loss-of-function mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8782815" 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>Studying 4 alkaptonuria patients from Slovakia, where alkaptonuria has a notably high frequency, <a href="#6" class="mim-tip-reference" title="Gehrig, A., Schmidt, S. R., Muller, C. R., Srsen, S., Srsnova, K., Kress, W. <strong>Molecular defects in alkaptonuria.</strong> Cytogenet. Cell Genet. 76: 14-16, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9154114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9154114</a>] [<a href="https://doi.org/10.1159/000134501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9154114">Gehrig et al. (1997)</a> found 2 novel mutations in the HGD gene. In 2 apparently unrelated patients, a 481G-A substitution was found leading to a gly161-to-arg amino acid substitution (<a href="#0003">607474.0003</a>). Both patients were the only affected members of their families and both were homozygous for this missense mutation. In another pedigree, 2 brothers were homozygous for a 1-basepair insertion (454-457insG) leading to a premature translational stop 26 codons downstream (<a href="#0004">607474.0004</a>); other relatives were heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9154114" 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="Beltran-Valero de Bernabe, D., Granadino, B., Chiarelli, I., Porfirio, B., Mayatepek, E., Aquaron, R., Moore, M. M., Festen, J. J. M., Sanmarti, R., Penalva, M. A., Rodriguez de Cordoba, S. <strong>Mutation and polymorphism analysis of the human homogentisate 1,2-dioxygenase gene in alkaptonuria patients.</strong> Am. J. Hum. Genet. 62: 776-784, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9529363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9529363</a>] [<a href="https://doi.org/10.1086/301805" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9529363">Beltran-Valero de Bernabe et al. (1998)</a> reported haplotype and mutation analysis of the HGO gene in 29 previously unstudied AKU chromosomes. They identified 12 novel mutations. Eight were missense mutations, 1 was a frameshift mutation, 2 were intronic mutations, and 1 was a splice site mutation. They also characterized 5 polymorphic sites in HGO and described the haplotypic associations of alleles at these sites in normal and AKU chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9529363" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Beltran-Valero de Bernabe, D., Jimenez, F. J., Aquaron, R., Rodriguez de Cordoba, S. <strong>Analysis of alkaptonuria (AKU) mutations and polymorphisms reveals that the CCC sequence motif is a mutational hot spot in the homogentisate 1,2 dioxygenase gene (HGO).</strong> Am. J. Hum. Genet. 64: 1316-1322, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10205262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10205262</a>] [<a href="https://doi.org/10.1086/302376" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10205262">Beltran-Valero de Bernabe et al. (1999)</a> stated that a total of 17 different AKU mutations had been described. Most of these were missense mutations changing amino acid residues that are conserved between human and other species. Only 3 had been found in more than 1 patient. This remarkable allelic heterogeneity was further demonstrated by analysis of 7 new AKU pedigrees, which uncovered 6 novel AKU mutations and 2 single-nucleotide polymorphisms. Reexamination of all 29 mutations and polymorphisms in the HGO gene described to that time showed that these nucleotide changes were not randomly distributed; the CCC sequence motif and its inverted complement, GGG, were preferentially mutated. These analyses also demonstrated that the nucleotide substitutions in the HGO gene did not involve CpG dinucleotides, which illustrates important differences between the HGO gene and other genes for the occurrence of mutation at specific short-sequence motifs. Because the CCC sequence motifs comprise a significant proportion (34.5%) of all mutated bases that have been observed in the HGO gene, <a href="#2" class="mim-tip-reference" title="Beltran-Valero de Bernabe, D., Jimenez, F. J., Aquaron, R., Rodriguez de Cordoba, S. <strong>Analysis of alkaptonuria (AKU) mutations and polymorphisms reveals that the CCC sequence motif is a mutational hot spot in the homogentisate 1,2 dioxygenase gene (HGO).</strong> Am. J. Hum. Genet. 64: 1316-1322, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10205262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10205262</a>] [<a href="https://doi.org/10.1086/302376" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10205262">Beltran-Valero de Bernabe et al. (1999)</a> concluded that the CCC triplet is a mutation hotspot in HGO. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10205262" 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="#3" class="mim-tip-reference" title="Beltran-Valero de Bernabe, D., Peterson, P., Luopajarvi, K., Matintalo, P., Alho, A., Konttinen, Y., Krohn, K., Rodriguez de Cordoba, S., Ranki, A. <strong>Mutational analysis of the HGO gene in Finnish alkaptonuria patients.</strong> J. Med. Genet. 36: 922-923, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10594001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10594001</a>]" pmid="10594001">Beltran-Valero de Bernabe et al. (1999)</a> reported 3 novel mutations (<a href="#0006">607474.0006</a>, <a href="#0007">607474.0007</a>, and <a href="#0008">607474.0008</a>) and 1 previously reported mutation, met368 to val (<a href="#0009">607474.0009</a>), in 2 Finnish alkaptonuria pedigrees. Using haplotype analysis, they predicted that the 3 novel mutations were most likely specific to the Finnish population and had arisen recently, in light of the low prevalence of alkaptonuria in Finland and the finding of homozygosity for these mutations in 3 individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10594001" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Muller, C. R., Fregin, A., Srsen, S., Srsnova, K., Halliger-Keller, B., Felbor, U., Seemanova, E., Kress, W. <strong>Allelic heterogeneity of alkaptonuria in Central Europe.</strong> Europ. J. Hum. Genet. 7: 645-651, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10482952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10482952</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200343" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10482952">Muller et al. (1999)</a> reported on the molecular defects in 30 AKU patients from central Europe. In addition to 5 mutations described previously, they detected 5 novel HGO mutations. In Slovakia, the country with the highest incidence of AKU, they found that 2 recurrent mutations, 183-1G to A (<a href="#0005">607474.0005</a>) and gly161 to arg (<a href="#0003">607474.0003</a>), were found on more than 50% of AKU chromosomes. An analysis of the allelic association with intragenic DNA markers and of the geographic origins of the AKU chromosomes suggested that several independent founders had contributed to the gene pool, and that subsequent genetic isolation was probably responsible for the high prevalence of alkaptonuria in Slovakia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10482952" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Rodriguez, J. M., Timm, D. E., Titus, G. P., Bertran-Valero de Bernabe, D., Criado, O., Mueller, H. A., Rodriguez de Cordoba, S., Penalva, M. A. <strong>Structural and functional analysis of mutations in alkaptonuria.</strong> Hum. Molec. Genet. 9: 2341-2350, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11001939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11001939</a>] [<a href="https://doi.org/10.1093/oxfordjournals.hmg.a018927" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11001939">Rodriguez et al. (2000)</a> reported 7 novel AKU and 22 fungal mutations, and correlated mutational information with HGO crystal structure and function using kinetic assays of AKU mutant enzymes. HGO is a topologically complex structure which assembles as a functional hexamer arranged as a dimer of trimers. The authors showed how the intra- and intersubunit interactions and the extensive surfaces required for subunit folding and association can be inactivated at multiple levels by single-residue substitutions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11001939" 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="#18" class="mim-tip-reference" title="Zatkova, A., Polakova, H., Micutkova, L., Zvarik, M., Bosak, V., Ferakova, E., Matusek, J., Ferak, V., Kadasi, L. <strong>Novel mutations in the homogentisate-1,2-dioxygenase gene identified in Slovak patients with alkaptonuria. (Letter)</strong> J. Med. Genet. 37: 539-542, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10970188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10970188</a>] [<a href="https://doi.org/10.1136/jmg.37.7.539" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10970188">Zatkova et al. (2000)</a> identified 9 different mutations in 32 chromosomes in 17 Slovak patients with alkaptonuria. Four mutations (2 missense, a frameshift, and a splice site mutation) were novel. Gly161 to arg (<a href="#0003">607474.0003</a>) and the 1-bp insertion at nucleotide 621 (<a href="#0010">607474.0010</a>) were each seen in 8 of 32 chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10970188" 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="Phornphutkul, C., Introne, W. J., Perry, M. B., Bernardini, I., Murphey, M. D., Fitzpatrick, D. L., Anderson, P. D., Huizing, M., Anikster, Y., Gerber, L. H., Gahl, W. A. <strong>Natural history of alkaptonuria.</strong> New Eng. J. Med. 347: 2111-2121, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12501223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12501223</a>] [<a href="https://doi.org/10.1056/NEJMoa021736" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12501223">Phornphutkul et al. (2002)</a> identified 23 new HGO mutations. In 57 patients, at least 1 HGO mutation was identified; 23 of these mutations had not previously been reported. Thirty-six patients were compound heterozygotes. In total, mutations were identified in 104 of 116 alleles. At least 1 M368V mutation (<a href="#0009">607474.0009</a>) occurred in 14 patients. Seven patients were also either homozygous or heterozygous for H80Q, which is considered a common polymorphism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12501223" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Zatkova, A., Chmelikova, A., Polakova, H., Ferakova, E., Kadasi, L. <strong>Rapid detection methods for five HGO gene mutations causing alkaptonuria.</strong> Clin. Genet. 63: 145-149, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12630963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12630963</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2003.00027.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12630963">Zatkova et al. (2003)</a> stated that 43 HGO mutations had been identified in approximately 100 patients. In Slovakia, the incidence of the disorder was estimated at 1 in 19,000, and 10 different AKU mutations had been identified in this relatively small country. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12630963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Vilboux, T., Kayser, M., Introne, W., Suwannarat, P., Bernardini, I., Fischer, R., O'Brien, K., Kleta, R., Huizing, M., Gahl, W. A. <strong>Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria.</strong> Hum. Mutat. 30: 1611-1619, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19862842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19862842</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19862842[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/10.1002/humu.21120" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19862842">Vilboux et al. (2009)</a> provided an extensive update of published HGD mutations associated with AKU and identified 52 variants in 93 additional patients. Twenty-two novel mutations were identified, yielding a total of 91 identified HGD variants associated with the disorder. Most of the variants occurred in exons 3, 6, 8, and 13. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19862842" 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 the course of an ethylnitrosourea mutation study, <a href="#8" class="mim-tip-reference" title="Guenet, J. L. <strong>Personal Communication.</strong> Paris, France 11/5/1990."None>Guenet (1990)</a> and his group detected a mutation for alkaptonuria in the mouse by the finding of black wood shavings in the mouse boxes.</p><p><a href="#9" class="mim-tip-reference" title="Manning, K., Fernandez-Canon, J. M., Montagutelli, X., Grompe, M. <strong>Identification of the mutation in the alkaptonuria mouse model. (Abstract)</strong> Hum. Mutat. 13: 171 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10094559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10094559</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1999)13:2<171::AID-HUMU15>3.0.CO;2-W" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10094559">Manning et al. (1999)</a> demonstrated that the mutation causing alkaptonuria in mice that was created by ethylnitrosourea mutagenesis was a single base change in a splice donor consensus sequence, causing exon skipping and frame-shifted products. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10094559" 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=607474[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<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> rs28942100 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28942100;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/rs28942100?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=rs28942100" 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=rs28942100" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#5" class="mim-tip-reference" title="Fernandez-Canon, J. M., Granadino, B., Beltran-Valero de Bernabe, D., Renedo, M., Fernandez-Ruiz, E., Penalva, M. A., Rodriguez de Cordoba, S. <strong>The molecular basis of alkaptonuria.</strong> Nature Genet. 14: 19-24, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782815</a>] [<a href="https://doi.org/10.1038/ng0996-19" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782815">Fernandez-Canon et al. (1996)</a> studied the HGD gene in 2 unrelated Spanish alkaptonuria (AKU; <a href="/entry/203500">203500</a>) pedigrees. The parents were not consanguineous. Each of the 14 exons composing the HGD gene was PCR-amplified and directly sequenced for each member of the 2 families. In family M, both parents were heterozygous at the HGD locus with a normal allele and an allele carrying a pro230-to-ser (P230S) mutation. The authors noted that pro230 is a conserved residue between the human and fungal proteins. The same 817C-T mutation was found in the second alkaptonuric family (S). The mother was heterozygous for the P230S mutation; the father was heterozygous for a novel allele determining a val300-to-gly substitution (V300G; <a href="#0002">607474.0002</a>). The substitution was determined by a 1028T-G transversion in exon 12. The val300 residue is also conserved between the fungal and human proteins. Three alkaptonuric children in this family S but none of 4 healthy children were compound heterozygotes carrying both 817C-T and 1028T-G mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8782815" 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 same P230S mutation that was found in the HGD gene in mainland Spanish pedigrees was found in an extensively affected kindred in the Canary Islands by <a href="#12" class="mim-tip-reference" title="Ramos, S. M., Hernandez, M., Roces, A., Larruga, J. M., Gonzalez, P., Gonzalez, A. M., Pinto, F. M., Cabrera, V. M. <strong>Molecular diagnosis of alkaptonuria mutation by analysis of homogentisate 1,2 dioxygenase mRNA from urine and blood.</strong> Am. J. Med. Genet. 78: 192-194, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9674916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9674916</a>]" pmid="9674916">Ramos et al. (1998)</a>. That they were not derived from the same ancestor, however, was suggested by the fact that the 817C-T transition was always associated with a 1219C-T synonymous substitution in the mainland families, which was not found in the Canarian AKU family. <a href="#12" class="mim-tip-reference" title="Ramos, S. M., Hernandez, M., Roces, A., Larruga, J. M., Gonzalez, P., Gonzalez, A. M., Pinto, F. M., Cabrera, V. M. <strong>Molecular diagnosis of alkaptonuria mutation by analysis of homogentisate 1,2 dioxygenase mRNA from urine and blood.</strong> Am. J. Med. Genet. 78: 192-194, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9674916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9674916</a>]" pmid="9674916">Ramos et al. (1998)</a> also demonstrated that as in the case with the phenylalanine hydroxylase gene (<a href="#15" class="mim-tip-reference" title="Takahashi, K., Kure, S., Matsubara, Y., Narisawa, K. <strong>Novel phenylketonuria mutation detected by analysis of ectopically transcribed phenylalanine hydroxylase mRNA from lymphoblast. (Letter)</strong> Lancet 340: 1473 only, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1360590/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1360590</a>] [<a href="https://doi.org/10.1016/0140-6736(92)92665-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1360590">Takahashi et al., 1992</a>), HGD mutations can be detected by ectopic or illegitimate transcription in tissues where the gene is normally not expressed, making the screening of new mutations easier. Reverse transcription-PCR was used for studying mRNA from urine and blood. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9674916+1360590" 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> rs120074170 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074170;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/rs120074170?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=rs120074170" 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=rs120074170" 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=RCV000003316" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003316" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003316</a>
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<p>For discussion of the val300-to-gly (V300G) mutation in the HGD gene that was found in compound heterozygous state in patients with alkaptonuria (AKU; <a href="/entry/203500">203500</a>) by <a href="#5" class="mim-tip-reference" title="Fernandez-Canon, J. M., Granadino, B., Beltran-Valero de Bernabe, D., Renedo, M., Fernandez-Ruiz, E., Penalva, M. A., Rodriguez de Cordoba, S. <strong>The molecular basis of alkaptonuria.</strong> Nature Genet. 14: 19-24, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782815</a>] [<a href="https://doi.org/10.1038/ng0996-19" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782815">Fernandez-Canon et al. (1996)</a>, see <a href="#0001">607474.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8782815" 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 ALKAPTONURIA</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> rs28941783 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28941783;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/rs28941783?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=rs28941783" 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=rs28941783" 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=RCV000003318 OR RCV001725928" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003318, RCV001725928" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003318...</a>
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<p>In 2 apparently unrelated Slovakian patients with alkaptonuria (AKU; <a href="/entry/203500">203500</a>), <a href="#6" class="mim-tip-reference" title="Gehrig, A., Schmidt, S. R., Muller, C. R., Srsen, S., Srsnova, K., Kress, W. <strong>Molecular defects in alkaptonuria.</strong> Cytogenet. Cell Genet. 76: 14-16, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9154114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9154114</a>] [<a href="https://doi.org/10.1159/000134501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9154114">Gehrig et al. (1997)</a> found homozygosity for a 481G-A transition of the HGD gene leading to a gly161-to-arg (G161R) amino acid substitution. <a href="#10" class="mim-tip-reference" title="Muller, C. R., Fregin, A., Srsen, S., Srsnova, K., Halliger-Keller, B., Felbor, U., Seemanova, E., Kress, W. <strong>Allelic heterogeneity of alkaptonuria in Central Europe.</strong> Europ. J. Hum. Genet. 7: 645-651, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10482952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10482952</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200343" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10482952">Muller et al. (1999)</a> found that the G161R substitution was the most prevalent AKU mutation in their cohort of Slovak and Czech patients, accounting for 39.5% of all disease alleles in 19 index patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9154114+10482952" 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="#18" class="mim-tip-reference" title="Zatkova, A., Polakova, H., Micutkova, L., Zvarik, M., Bosak, V., Ferakova, E., Matusek, J., Ferak, V., Kadasi, L. <strong>Novel mutations in the homogentisate-1,2-dioxygenase gene identified in Slovak patients with alkaptonuria. (Letter)</strong> J. Med. Genet. 37: 539-542, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10970188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10970188</a>] [<a href="https://doi.org/10.1136/jmg.37.7.539" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10970188">Zatkova et al. (2000)</a> identified this mutation in 8 of 32 chromosomes studied from a Slovak population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10970188" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 ALKAPTONURIA</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> rs397515346 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515346;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/rs397515346?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=rs397515346" 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=rs397515346" 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=RCV000003319" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003319" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003319</a>
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<p>In a Slovakian family with 2 brothers affected with alkaptonuria (AKU; <a href="/entry/203500">203500</a>), <a href="#6" class="mim-tip-reference" title="Gehrig, A., Schmidt, S. R., Muller, C. R., Srsen, S., Srsnova, K., Kress, W. <strong>Molecular defects in alkaptonuria.</strong> Cytogenet. Cell Genet. 76: 14-16, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9154114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9154114</a>] [<a href="https://doi.org/10.1159/000134501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9154114">Gehrig et al. (1997)</a> found a 1-bp insertion (454-457insG) in exon 7 of the HGD gene, which led to a premature translational stop 26 codons downstream. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9154114" 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="0005" class="mim-anchor"></a>
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<strong>.0005 ALKAPTONURIA</strong>
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HGD, IVS1AS, 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"><span class="text-primary">●</span> rs397515347 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515347;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/rs397515347?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=rs397515347" 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=rs397515347" 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=RCV000003320 OR RCV004597723 OR RCV004751195" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003320, RCV004597723, RCV004751195" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003320...</a>
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<p>In 5 alkaptonuria (AKU; <a href="/entry/203500">203500</a>) patients of Slovak and Czech origin, <a href="#10" class="mim-tip-reference" title="Muller, C. R., Fregin, A., Srsen, S., Srsnova, K., Halliger-Keller, B., Felbor, U., Seemanova, E., Kress, W. <strong>Allelic heterogeneity of alkaptonuria in Central Europe.</strong> Europ. J. Hum. Genet. 7: 645-651, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10482952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10482952</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200343" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10482952">Muller et al. (1999)</a> found an exchange of the first nucleotide of the splice acceptor site in intron 1 of the HGO gene (183-1G-A), which was likely to abolish effective splicing of exon 2. This was the second most frequent mutation seen in their cohort (the first being G161R, <a href="#0003">607474.0003</a>), representing 13% of all independent AKU alleles studied. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10482952" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 ALKAPTONURIA</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">rs397515517 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515517;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=rs397515517" 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=rs397515517" 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=RCV000003321 OR RCV001169911" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003321, RCV001169911" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003321...</a>
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<p>In a single Finnish pedigree with alkaptonuria (AKU; <a href="/entry/203500">203500</a>), <a href="#3" class="mim-tip-reference" title="Beltran-Valero de Bernabe, D., Peterson, P., Luopajarvi, K., Matintalo, P., Alho, A., Konttinen, Y., Krohn, K., Rodriguez de Cordoba, S., Ranki, A. <strong>Mutational analysis of the HGO gene in Finnish alkaptonuria patients.</strong> J. Med. Genet. 36: 922-923, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10594001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10594001</a>]" pmid="10594001">Beltran-Valero de Bernabe et al. (1999)</a> reported a 1-bp deletion at nucleotide 342 resulting in a frameshift with translation of the first 58 amino acids of the normal HGD protein followed by 31 unrelated amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10594001" 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>See also <a href="#0011">607474.0011</a> and <a href="#4" class="mim-tip-reference" title="Elcioglu, N. H., Aytug, A. F., Muller, C. R., Gurbuz, O., Ergun, T., Kotiloglu E., Elcioglu, M. <strong>Alkaptonuria caused by compound heterozygote mutations.</strong> Genet. Counsel. 14: 207-213, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12872815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12872815</a>]" pmid="12872815">Elcioglu et al. (2003)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12872815" 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="0007" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0007 ALKAPTONURIA</strong>
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HGD, ARG330SER
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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> rs120074171 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074171;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/rs120074171?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=rs120074171" 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=rs120074171" 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=RCV000003317" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003317" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003317</a>
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<p>In a single Finnish pedigree with alkaptonuria (AKU; <a href="/entry/203500">203500</a>), <a href="#3" class="mim-tip-reference" title="Beltran-Valero de Bernabe, D., Peterson, P., Luopajarvi, K., Matintalo, P., Alho, A., Konttinen, Y., Krohn, K., Rodriguez de Cordoba, S., Ranki, A. <strong>Mutational analysis of the HGO gene in Finnish alkaptonuria patients.</strong> J. Med. Genet. 36: 922-923, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10594001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10594001</a>]" pmid="10594001">Beltran-Valero de Bernabe et al. (1999)</a> reported an G-to-T transversion at nucleotide 1157 of the HGD gene, resulting in the substitution of a serine in place of a highly conserved arginine residue at codon 330 (R330S). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10594001" 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> rs120074172 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074172;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/rs120074172?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=rs120074172" 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=rs120074172" 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=RCV000003322" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003322" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003322</a>
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<p>In a single Finnish pedigree with alkaptonuria (AKU; <a href="/entry/203500">203500</a>), <a href="#3" class="mim-tip-reference" title="Beltran-Valero de Bernabe, D., Peterson, P., Luopajarvi, K., Matintalo, P., Alho, A., Konttinen, Y., Krohn, K., Rodriguez de Cordoba, S., Ranki, A. <strong>Mutational analysis of the HGO gene in Finnish alkaptonuria patients.</strong> J. Med. Genet. 36: 922-923, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10594001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10594001</a>]" pmid="10594001">Beltran-Valero de Bernabe et al. (1999)</a> reported an A-to-G transition at nucleotide 1279, resulting in the substitution of an arginine in place of a highly conserved histidine residue at codon 371 (H371R). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10594001" 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 ALKAPTONURIA</strong>
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HGD, MET368VAL
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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> rs120074173 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074173;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/rs120074173?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=rs120074173" 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=rs120074173" 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=RCV000003323 OR RCV002279945 OR RCV004584308" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003323, RCV002279945, RCV004584308" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003323...</a>
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<p>In 2 families with alkaptonuria (AKU; <a href="/entry/203500">203500</a>), one from Germany and the other from France, <a href="#1" class="mim-tip-reference" title="Beltran-Valero de Bernabe, D., Granadino, B., Chiarelli, I., Porfirio, B., Mayatepek, E., Aquaron, R., Moore, M. M., Festen, J. J. M., Sanmarti, R., Penalva, M. A., Rodriguez de Cordoba, S. <strong>Mutation and polymorphism analysis of the human homogentisate 1,2-dioxygenase gene in alkaptonuria patients.</strong> Am. J. Hum. Genet. 62: 776-784, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9529363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9529363</a>] [<a href="https://doi.org/10.1086/301805" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9529363">Beltran-Valero de Bernabe et al. (1998)</a> identified an A-to-G transition at nucleotide position 1269 of the HGD gene, which resulted in the substitution of valine for a highly conserved methionine at codon 368 (M368V). <a href="#3" class="mim-tip-reference" title="Beltran-Valero de Bernabe, D., Peterson, P., Luopajarvi, K., Matintalo, P., Alho, A., Konttinen, Y., Krohn, K., Rodriguez de Cordoba, S., Ranki, A. <strong>Mutational analysis of the HGO gene in Finnish alkaptonuria patients.</strong> J. Med. Genet. 36: 922-923, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10594001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10594001</a>]" pmid="10594001">Beltran-Valero de Bernabe et al. (1999)</a> found this mutation in 2 Finnish families. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10594001+9529363" 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 ALKAPTONURIA</strong>
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HGD, 1-BP INS, 621G
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003319" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003319" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003319</a>
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<p>In 8 of 32 alkaptonuria (AKU; <a href="/entry/203500">203500</a>) chromosomes studied in a Slovak population, <a href="#18" class="mim-tip-reference" title="Zatkova, A., Polakova, H., Micutkova, L., Zvarik, M., Bosak, V., Ferakova, E., Matusek, J., Ferak, V., Kadasi, L. <strong>Novel mutations in the homogentisate-1,2-dioxygenase gene identified in Slovak patients with alkaptonuria. (Letter)</strong> J. Med. Genet. 37: 539-542, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10970188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10970188</a>] [<a href="https://doi.org/10.1136/jmg.37.7.539" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10970188">Zatkova et al. (2000)</a> identified a 1-bp insertion at nucleotide 621 of the HGD gene, resulting in frameshift. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10970188" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 ALKAPTONURIA</strong>
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HGD, GLY270ARG
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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> rs120074174 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074174;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/rs120074174?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=rs120074174" 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=rs120074174" 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=RCV000003325" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003325" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003325</a>
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<p>In Turkey, <a href="#4" class="mim-tip-reference" title="Elcioglu, N. H., Aytug, A. F., Muller, C. R., Gurbuz, O., Ergun, T., Kotiloglu E., Elcioglu, M. <strong>Alkaptonuria caused by compound heterozygote mutations.</strong> Genet. Counsel. 14: 207-213, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12872815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12872815</a>]" pmid="12872815">Elcioglu et al. (2003)</a> described a 39-year-old male patient with typical features of alkaptonuria (AKU; <a href="/entry/203500">203500</a>). In addition to the typical changes in the skin at many sites and in the pinnae and sclerae, there were grayish-blue longitudinal rigging of his fingernails and bluish-gray pigment deposition on the tympanic membrane. He was found to be compound heterozygous for 2 mutations in the HGD gene: gly270 to arg (G270R) in exon 11 and 342delA (<a href="#0006">607474.0006</a>) in exon 3 leading to a frameshift after arg58 and a subsequent premature stop codon. Both mutations had been described in other AKU patients and shown experimentally to reduce HGD activity to near null (<a href="#10" class="mim-tip-reference" title="Muller, C. R., Fregin, A., Srsen, S., Srsnova, K., Halliger-Keller, B., Felbor, U., Seemanova, E., Kress, W. <strong>Allelic heterogeneity of alkaptonuria in Central Europe.</strong> Europ. J. Hum. Genet. 7: 645-651, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10482952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10482952</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200343" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10482952">Muller et al., 1999</a>; <a href="#13" class="mim-tip-reference" title="Rodriguez, J. M., Timm, D. E., Titus, G. P., Bertran-Valero de Bernabe, D., Criado, O., Mueller, H. A., Rodriguez de Cordoba, S., Penalva, M. A. <strong>Structural and functional analysis of mutations in alkaptonuria.</strong> Hum. Molec. Genet. 9: 2341-2350, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11001939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11001939</a>] [<a href="https://doi.org/10.1093/oxfordjournals.hmg.a018927" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11001939">Rodriguez et al., 2000</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11001939+10482952+12872815" 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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Beltran-Valero de Bernabe, D., Granadino, B., Chiarelli, I., Porfirio, B., Mayatepek, E., Aquaron, R., Moore, M. M., Festen, J. J. M., Sanmarti, R., Penalva, M. A., Rodriguez de Cordoba, S.
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<strong>Mutation and polymorphism analysis of the human homogentisate 1,2-dioxygenase gene in alkaptonuria patients.</strong>
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Am. J. Hum. Genet. 62: 776-784, 1998.
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<span class="mim-text-font">
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Matthew B. Gross - updated : 4/25/2014
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 4/21/2014<br>Victor A. McKusick - updated : 9/12/2003<br>Victor A. McKusick - updated : 4/22/2003
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Creation Date:
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<span class="mim-text-font">
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Cassandra L. Kniffin : 1/13/2003
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carol : 05/08/2015
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<span class="mim-text-font">
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mcolton : 5/5/2015<br>mgross : 4/25/2014<br>mcolton : 4/23/2014<br>carol : 4/22/2014<br>mcolton : 4/21/2014<br>ckniffin : 4/21/2014<br>carol : 2/8/2006<br>terry : 8/3/2005<br>cwells : 9/12/2003<br>tkritzer : 4/28/2003<br>terry : 4/22/2003<br>carol : 1/15/2003<br>ckniffin : 1/14/2003
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<span class="mim-font">
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<strong>*</strong> 607474
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<h3>
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HOMOGENTISATE 1,2-DIOXYGENASE; HGD
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<span class="mim-font">
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HOMOGENTISIC ACID OXIDASE; HGO
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: HGD</em></strong>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 360378009;
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<strong>ICD10CM:</strong> E70.29;
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<strong>
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<em>
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Cytogenetic location: 3q13.33
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Genomic coordinates <span class="small">(GRCh38)</span> : 3:120,628,172-120,682,239 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<td rowspan="1">
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<span class="mim-font">
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3q13.33
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<span class="mim-font">
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Alkaptonuria
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<span class="mim-font">
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203500
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<span class="mim-font">
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Autosomal recessive
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<span class="mim-font">
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<strong>Description</strong>
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<span class="mim-text-font">
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<p>The HGD gene encodes homogentisate 1,2-dioxygenase (HGD; EC 1.13.11.5), an enzyme involved in the catabolism of phenylalanine and tyrosine (summary by Vilboux et al., 2009). </p>
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<h4>
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<strong>Cloning and Expression</strong>
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<p>Fernandez-Canon et al. (1996) cloned the gene for homogentisate 1,2-dioxygenase. Characterization of the human HGD gene came from work with the ascomycete fungus Aspergillus nidulans in which a gene encoding an HGD enzyme, hmgA, had been cloned. The deduced amino acid sequence of its encoded protein product was used to identify EST clones putatively corresponding to the human HGD gene. HGD encodes a 445-amino acid polypeptide with high homology to the Aspergillus hmgA. By Northern blot analysis, Fernandez-Canon et al. (1996) found highest expression of HGD in the prostate, small intestine, colon, and liver. </p><p>Schmidt et al. (1997) cloned the homogentisate 1,2-dioxygenase gene in the mouse. </p>
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<h4>
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<strong>Gene Structure</strong>
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<span class="mim-text-font">
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<p>Fernandez-Canon et al. (1996) determined that the HGD gene contains 14 exons. </p>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</div>
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<span class="mim-text-font">
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<p>Fernandez-Canon et al. (1996) mapped the HGD gene to chromosome 3q21-q23 by a preliminary PCR screen of hamster/human somatic cell hybrid genomic DNA samples and by fluorescence in situ hybridization. </p><p>Gross (2014) mapped the HGD gene to chromosome 3q13.33 based on an alignment of the HGD sequence (GenBank AF000573) with the genomic sequence (GRCh37).</p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p>In patients with alkaptonuria (AKU; 203500), Fernandez-Canon et al. (1996) identified missense mutations in the HGD gene that cosegregated with the disease (607474.0001, 607474.0002), and provided biochemical evidence that at least one of these missense mutations is a loss-of-function mutation. </p><p>Studying 4 alkaptonuria patients from Slovakia, where alkaptonuria has a notably high frequency, Gehrig et al. (1997) found 2 novel mutations in the HGD gene. In 2 apparently unrelated patients, a 481G-A substitution was found leading to a gly161-to-arg amino acid substitution (607474.0003). Both patients were the only affected members of their families and both were homozygous for this missense mutation. In another pedigree, 2 brothers were homozygous for a 1-basepair insertion (454-457insG) leading to a premature translational stop 26 codons downstream (607474.0004); other relatives were heterozygous for the mutation. </p><p>Beltran-Valero de Bernabe et al. (1998) reported haplotype and mutation analysis of the HGO gene in 29 previously unstudied AKU chromosomes. They identified 12 novel mutations. Eight were missense mutations, 1 was a frameshift mutation, 2 were intronic mutations, and 1 was a splice site mutation. They also characterized 5 polymorphic sites in HGO and described the haplotypic associations of alleles at these sites in normal and AKU chromosomes. </p><p>Beltran-Valero de Bernabe et al. (1999) stated that a total of 17 different AKU mutations had been described. Most of these were missense mutations changing amino acid residues that are conserved between human and other species. Only 3 had been found in more than 1 patient. This remarkable allelic heterogeneity was further demonstrated by analysis of 7 new AKU pedigrees, which uncovered 6 novel AKU mutations and 2 single-nucleotide polymorphisms. Reexamination of all 29 mutations and polymorphisms in the HGO gene described to that time showed that these nucleotide changes were not randomly distributed; the CCC sequence motif and its inverted complement, GGG, were preferentially mutated. These analyses also demonstrated that the nucleotide substitutions in the HGO gene did not involve CpG dinucleotides, which illustrates important differences between the HGO gene and other genes for the occurrence of mutation at specific short-sequence motifs. Because the CCC sequence motifs comprise a significant proportion (34.5%) of all mutated bases that have been observed in the HGO gene, Beltran-Valero de Bernabe et al. (1999) concluded that the CCC triplet is a mutation hotspot in HGO. </p><p>Beltran-Valero de Bernabe et al. (1999) reported 3 novel mutations (607474.0006, 607474.0007, and 607474.0008) and 1 previously reported mutation, met368 to val (607474.0009), in 2 Finnish alkaptonuria pedigrees. Using haplotype analysis, they predicted that the 3 novel mutations were most likely specific to the Finnish population and had arisen recently, in light of the low prevalence of alkaptonuria in Finland and the finding of homozygosity for these mutations in 3 individuals. </p><p>Muller et al. (1999) reported on the molecular defects in 30 AKU patients from central Europe. In addition to 5 mutations described previously, they detected 5 novel HGO mutations. In Slovakia, the country with the highest incidence of AKU, they found that 2 recurrent mutations, 183-1G to A (607474.0005) and gly161 to arg (607474.0003), were found on more than 50% of AKU chromosomes. An analysis of the allelic association with intragenic DNA markers and of the geographic origins of the AKU chromosomes suggested that several independent founders had contributed to the gene pool, and that subsequent genetic isolation was probably responsible for the high prevalence of alkaptonuria in Slovakia. </p><p>Rodriguez et al. (2000) reported 7 novel AKU and 22 fungal mutations, and correlated mutational information with HGO crystal structure and function using kinetic assays of AKU mutant enzymes. HGO is a topologically complex structure which assembles as a functional hexamer arranged as a dimer of trimers. The authors showed how the intra- and intersubunit interactions and the extensive surfaces required for subunit folding and association can be inactivated at multiple levels by single-residue substitutions. </p><p>Zatkova et al. (2000) identified 9 different mutations in 32 chromosomes in 17 Slovak patients with alkaptonuria. Four mutations (2 missense, a frameshift, and a splice site mutation) were novel. Gly161 to arg (607474.0003) and the 1-bp insertion at nucleotide 621 (607474.0010) were each seen in 8 of 32 chromosomes. </p><p>Phornphutkul et al. (2002) identified 23 new HGO mutations. In 57 patients, at least 1 HGO mutation was identified; 23 of these mutations had not previously been reported. Thirty-six patients were compound heterozygotes. In total, mutations were identified in 104 of 116 alleles. At least 1 M368V mutation (607474.0009) occurred in 14 patients. Seven patients were also either homozygous or heterozygous for H80Q, which is considered a common polymorphism. </p><p>Zatkova et al. (2003) stated that 43 HGO mutations had been identified in approximately 100 patients. In Slovakia, the incidence of the disorder was estimated at 1 in 19,000, and 10 different AKU mutations had been identified in this relatively small country. </p><p>Vilboux et al. (2009) provided an extensive update of published HGD mutations associated with AKU and identified 52 variants in 93 additional patients. Twenty-two novel mutations were identified, yielding a total of 91 identified HGD variants associated with the disorder. Most of the variants occurred in exons 3, 6, 8, and 13. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In the course of an ethylnitrosourea mutation study, Guenet (1990) and his group detected a mutation for alkaptonuria in the mouse by the finding of black wood shavings in the mouse boxes.</p><p>Manning et al. (1999) demonstrated that the mutation causing alkaptonuria in mice that was created by ethylnitrosourea mutagenesis was a single base change in a splice donor consensus sequence, causing exon skipping and frame-shifted products. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>11 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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<h4>
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<span class="mim-font">
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<strong>.0001 ALKAPTONURIA</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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HGD, PRO230SER
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<br />
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SNP: rs28942100,
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gnomAD: rs28942100,
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ClinVar: RCV000003315
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<span class="mim-text-font">
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<p>Fernandez-Canon et al. (1996) studied the HGD gene in 2 unrelated Spanish alkaptonuria (AKU; 203500) pedigrees. The parents were not consanguineous. Each of the 14 exons composing the HGD gene was PCR-amplified and directly sequenced for each member of the 2 families. In family M, both parents were heterozygous at the HGD locus with a normal allele and an allele carrying a pro230-to-ser (P230S) mutation. The authors noted that pro230 is a conserved residue between the human and fungal proteins. The same 817C-T mutation was found in the second alkaptonuric family (S). The mother was heterozygous for the P230S mutation; the father was heterozygous for a novel allele determining a val300-to-gly substitution (V300G; 607474.0002). The substitution was determined by a 1028T-G transversion in exon 12. The val300 residue is also conserved between the fungal and human proteins. Three alkaptonuric children in this family S but none of 4 healthy children were compound heterozygotes carrying both 817C-T and 1028T-G mutations. </p><p>The same P230S mutation that was found in the HGD gene in mainland Spanish pedigrees was found in an extensively affected kindred in the Canary Islands by Ramos et al. (1998). That they were not derived from the same ancestor, however, was suggested by the fact that the 817C-T transition was always associated with a 1219C-T synonymous substitution in the mainland families, which was not found in the Canarian AKU family. Ramos et al. (1998) also demonstrated that as in the case with the phenylalanine hydroxylase gene (Takahashi et al., 1992), HGD mutations can be detected by ectopic or illegitimate transcription in tissues where the gene is normally not expressed, making the screening of new mutations easier. Reverse transcription-PCR was used for studying mRNA from urine and blood. </p>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 ALKAPTONURIA</strong>
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<span class="mim-text-font">
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HGD, VAL300GLY
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<br />
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SNP: rs120074170,
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gnomAD: rs120074170,
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ClinVar: RCV000003316
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<span class="mim-text-font">
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<p>For discussion of the val300-to-gly (V300G) mutation in the HGD gene that was found in compound heterozygous state in patients with alkaptonuria (AKU; 203500) by Fernandez-Canon et al. (1996), see 607474.0001. </p>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0003 ALKAPTONURIA</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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HGD, GLY161ARG
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<br />
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|
|
SNP: rs28941783,
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|
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gnomAD: rs28941783,
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|
|
ClinVar: RCV000003318, RCV001725928
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 2 apparently unrelated Slovakian patients with alkaptonuria (AKU; 203500), Gehrig et al. (1997) found homozygosity for a 481G-A transition of the HGD gene leading to a gly161-to-arg (G161R) amino acid substitution. Muller et al. (1999) found that the G161R substitution was the most prevalent AKU mutation in their cohort of Slovak and Czech patients, accounting for 39.5% of all disease alleles in 19 index patients. </p><p>Zatkova et al. (2000) identified this mutation in 8 of 32 chromosomes studied from a Slovak population. </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>.0004 ALKAPTONURIA</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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HGD, 1-BP INS, 454G
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<br />
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SNP: rs397515346,
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gnomAD: rs397515346,
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ClinVar: RCV000003319
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Slovakian family with 2 brothers affected with alkaptonuria (AKU; 203500), Gehrig et al. (1997) found a 1-bp insertion (454-457insG) in exon 7 of the HGD gene, which led to a premature translational stop 26 codons downstream. </p>
|
|
</span>
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|
</div>
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<div>
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<br />
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|
</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 ALKAPTONURIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
HGD, IVS1AS, G-A, -1
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<br />
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|
|
SNP: rs397515347,
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|
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|
|
gnomAD: rs397515347,
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|
|
ClinVar: RCV000003320, RCV004597723, RCV004751195
|
|
|
|
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 alkaptonuria (AKU; 203500) patients of Slovak and Czech origin, Muller et al. (1999) found an exchange of the first nucleotide of the splice acceptor site in intron 1 of the HGO gene (183-1G-A), which was likely to abolish effective splicing of exon 2. This was the second most frequent mutation seen in their cohort (the first being G161R, 607474.0003), representing 13% of all independent AKU alleles studied. </p>
|
|
</span>
|
|
</div>
|
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|
<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 ALKAPTONURIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
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|
HGD, 1-BP DEL, 342A
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|
|
<br />
|
|
|
|
SNP: rs397515517,
|
|
|
|
|
|
|
|
ClinVar: RCV000003321, RCV001169911
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a single Finnish pedigree with alkaptonuria (AKU; 203500), Beltran-Valero de Bernabe et al. (1999) reported a 1-bp deletion at nucleotide 342 resulting in a frameshift with translation of the first 58 amino acids of the normal HGD protein followed by 31 unrelated amino acids. </p><p>See also 607474.0011 and Elcioglu et al. (2003). </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
</div>
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 ALKAPTONURIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
HGD, ARG330SER
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|
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<br />
|
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|
|
SNP: rs120074171,
|
|
|
|
|
|
gnomAD: rs120074171,
|
|
|
|
|
|
ClinVar: RCV000003317
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a single Finnish pedigree with alkaptonuria (AKU; 203500), Beltran-Valero de Bernabe et al. (1999) reported an G-to-T transversion at nucleotide 1157 of the HGD gene, resulting in the substitution of a serine in place of a highly conserved arginine residue at codon 330 (R330S). </p>
|
|
</span>
|
|
</div>
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 ALKAPTONURIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HGD, HIS371ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs120074172,
|
|
|
|
|
|
gnomAD: rs120074172,
|
|
|
|
|
|
ClinVar: RCV000003322
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a single Finnish pedigree with alkaptonuria (AKU; 203500), Beltran-Valero de Bernabe et al. (1999) reported an A-to-G transition at nucleotide 1279, resulting in the substitution of an arginine in place of a highly conserved histidine residue at codon 371 (H371R). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 ALKAPTONURIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HGD, MET368VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs120074173,
|
|
|
|
|
|
gnomAD: rs120074173,
|
|
|
|
|
|
ClinVar: RCV000003323, RCV002279945, RCV004584308
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 families with alkaptonuria (AKU; 203500), one from Germany and the other from France, Beltran-Valero de Bernabe et al. (1998) identified an A-to-G transition at nucleotide position 1269 of the HGD gene, which resulted in the substitution of valine for a highly conserved methionine at codon 368 (M368V). Beltran-Valero de Bernabe et al. (1999) found this mutation in 2 Finnish families. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 ALKAPTONURIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HGD, 1-BP INS, 621G
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000003319
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 8 of 32 alkaptonuria (AKU; 203500) chromosomes studied in a Slovak population, Zatkova et al. (2000) identified a 1-bp insertion at nucleotide 621 of the HGD gene, resulting in frameshift. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 ALKAPTONURIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HGD, GLY270ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs120074174,
|
|
|
|
|
|
gnomAD: rs120074174,
|
|
|
|
|
|
ClinVar: RCV000003325
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Turkey, Elcioglu et al. (2003) described a 39-year-old male patient with typical features of alkaptonuria (AKU; 203500). In addition to the typical changes in the skin at many sites and in the pinnae and sclerae, there were grayish-blue longitudinal rigging of his fingernails and bluish-gray pigment deposition on the tympanic membrane. He was found to be compound heterozygous for 2 mutations in the HGD gene: gly270 to arg (G270R) in exon 11 and 342delA (607474.0006) in exon 3 leading to a frameshift after arg58 and a subsequent premature stop codon. Both mutations had been described in other AKU patients and shown experimentally to reduce HGD activity to near null (Muller et al., 1999; Rodriguez et al., 2000). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
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|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Beltran-Valero de Bernabe, D., Granadino, B., Chiarelli, I., Porfirio, B., Mayatepek, E., Aquaron, R., Moore, M. M., Festen, J. J. M., Sanmarti, R., Penalva, M. A., Rodriguez de Cordoba, S.
|
|
<strong>Mutation and polymorphism analysis of the human homogentisate 1,2-dioxygenase gene in alkaptonuria patients.</strong>
|
|
Am. J. Hum. Genet. 62: 776-784, 1998.
|
|
|
|
|
|
[PubMed: 9529363]
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|
|
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|
|
[Full Text: https://doi.org/10.1086/301805]
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Beltran-Valero de Bernabe, D., Jimenez, F. J., Aquaron, R., Rodriguez de Cordoba, S.
|
|
<strong>Analysis of alkaptonuria (AKU) mutations and polymorphisms reveals that the CCC sequence motif is a mutational hot spot in the homogentisate 1,2 dioxygenase gene (HGO).</strong>
|
|
Am. J. Hum. Genet. 64: 1316-1322, 1999.
|
|
|
|
|
|
[PubMed: 10205262]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1086/302376]
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</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Beltran-Valero de Bernabe, D., Peterson, P., Luopajarvi, K., Matintalo, P., Alho, A., Konttinen, Y., Krohn, K., Rodriguez de Cordoba, S., Ranki, A.
|
|
<strong>Mutational analysis of the HGO gene in Finnish alkaptonuria patients.</strong>
|
|
J. Med. Genet. 36: 922-923, 1999.
|
|
|
|
|
|
[PubMed: 10594001]
|
|
|
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Elcioglu, N. H., Aytug, A. F., Muller, C. R., Gurbuz, O., Ergun, T., Kotiloglu E., Elcioglu, M.
|
|
<strong>Alkaptonuria caused by compound heterozygote mutations.</strong>
|
|
Genet. Counsel. 14: 207-213, 2003.
|
|
|
|
|
|
[PubMed: 12872815]
|
|
|
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|
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</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Fernandez-Canon, J. M., Granadino, B., Beltran-Valero de Bernabe, D., Renedo, M., Fernandez-Ruiz, E., Penalva, M. A., Rodriguez de Cordoba, S.
|
|
<strong>The molecular basis of alkaptonuria.</strong>
|
|
Nature Genet. 14: 19-24, 1996.
|
|
|
|
|
|
[PubMed: 8782815]
|
|
|
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|
|
[Full Text: https://doi.org/10.1038/ng0996-19]
|
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gehrig, A., Schmidt, S. R., Muller, C. R., Srsen, S., Srsnova, K., Kress, W.
|
|
<strong>Molecular defects in alkaptonuria.</strong>
|
|
Cytogenet. Cell Genet. 76: 14-16, 1997.
|
|
|
|
|
|
[PubMed: 9154114]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1159/000134501]
|
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gross, M. B.
|
|
<strong>Personal Communication.</strong>
|
|
Baltimore, Md. 4/25/2014.
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Guenet, J. L.
|
|
<strong>Personal Communication.</strong>
|
|
Paris, France 11/5/1990.
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Manning, K., Fernandez-Canon, J. M., Montagutelli, X., Grompe, M.
|
|
<strong>Identification of the mutation in the alkaptonuria mouse model. (Abstract)</strong>
|
|
Hum. Mutat. 13: 171 only, 1999.
|
|
|
|
|
|
[PubMed: 10094559]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/(SICI)1098-1004(1999)13:2<171::AID-HUMU15>3.0.CO;2-W]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Muller, C. R., Fregin, A., Srsen, S., Srsnova, K., Halliger-Keller, B., Felbor, U., Seemanova, E., Kress, W.
|
|
<strong>Allelic heterogeneity of alkaptonuria in Central Europe.</strong>
|
|
Europ. J. Hum. Genet. 7: 645-651, 1999.
|
|
|
|
|
|
[PubMed: 10482952]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/sj.ejhg.5200343]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Phornphutkul, C., Introne, W. J., Perry, M. B., Bernardini, I., Murphey, M. D., Fitzpatrick, D. L., Anderson, P. D., Huizing, M., Anikster, Y., Gerber, L. H., Gahl, W. A.
|
|
<strong>Natural history of alkaptonuria.</strong>
|
|
New Eng. J. Med. 347: 2111-2121, 2002.
|
|
|
|
|
|
[PubMed: 12501223]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1056/NEJMoa021736]
|
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ramos, S. M., Hernandez, M., Roces, A., Larruga, J. M., Gonzalez, P., Gonzalez, A. M., Pinto, F. M., Cabrera, V. M.
|
|
<strong>Molecular diagnosis of alkaptonuria mutation by analysis of homogentisate 1,2 dioxygenase mRNA from urine and blood.</strong>
|
|
Am. J. Med. Genet. 78: 192-194, 1998.
|
|
|
|
|
|
[PubMed: 9674916]
|
|
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
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Takahashi, K., Kure, S., Matsubara, Y., Narisawa, K.
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<strong>Novel phenylketonuria mutation detected by analysis of ectopically transcribed phenylalanine hydroxylase mRNA from lymphoblast. (Letter)</strong>
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Vilboux, T., Kayser, M., Introne, W., Suwannarat, P., Bernardini, I., Fischer, R., O'Brien, K., Kleta, R., Huizing, M., Gahl, W. A.
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Zatkova, A., Chmelikova, A., Polakova, H., Ferakova, E., Kadasi, L.
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<strong>Rapid detection methods for five HGO gene mutations causing alkaptonuria.</strong>
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Zatkova, A., Polakova, H., Micutkova, L., Zvarik, M., Bosak, V., Ferakova, E., Matusek, J., Ferak, V., Kadasi, L.
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Matthew B. Gross - updated : 4/25/2014<br>Cassandra L. Kniffin - updated : 4/21/2014<br>Victor A. McKusick - updated : 9/12/2003<br>Victor A. McKusick - updated : 4/22/2003
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