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Entry
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- *300461 - ORNITHINE CARBAMOYLTRANSFERASE; OTC
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*300461</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<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="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/300461">Table View</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<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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<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=ENSG00000036473;t=ENST00000039007" 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=5009" 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=300461" 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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<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=ENSG00000036473;t=ENST00000039007" 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_000531,NM_001407092,XM_017029556" 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_000531" 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=300461" 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=08947&isoform_id=08947_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/OTC" 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/35163,189407,189409,219959,219961,688002,38788445,50960303,76825399,76827284,84028235,109730335,119579843,119579844,158258951,1034674430,2244985418,2462629628" 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/P00480" 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=5009" 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=ENSG00000036473;t=ENST00000039007" 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=OTC" 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=OTC" 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+5009" 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/OTC" 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:5009" 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/5009" 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=chrX&hgg_gene=ENST00000039007.5&hgg_start=38327684&hgg_end=38422928&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/gene-dosage/HGNC:8512" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:8512" 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/otc" 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=300461[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=300461[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://www.deciphergenomics.org/gene/OTC/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000036473" 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=OTC" 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=OTC" 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=OTC" 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="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://ureacycle.cnmcresearch.org/otc/" title="Ornithine Transcarbamylase Deficiency Website" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Ornithine Transcarbamylase…</a></div><div style="margin-left: 0.5em;"><a href="http://www.LOVD.nl/OTC" title="OTC - Ornithine transcarbamylase deficiency" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">OTC - Ornithine transcarba…</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=OTC&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/PA32840" 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:8512" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:97448" 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/OTC#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:97448" 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/5009/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/OMIA002383/" 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=5009" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-070912-422" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
|
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</div>
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</a>
|
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:5009" 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=OTC&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> 80908008<br />
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<strong>ICD10CM:</strong> E72.4<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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300461
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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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|
ORNITHINE CARBAMOYLTRANSFERASE; OTC
|
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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>
|
|
<span class="mim-font">
|
|
ORNITHINE TRANSCARBAMYLASE
|
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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>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=OTC" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">OTC</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>
|
|
Cytogenetic location: <a href="/geneMap/X/169?start=-3&limit=10&highlight=169">Xp11.4</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chrX:38327684-38422928&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'})">X:38,327,684-38,422,928</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<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>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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</th>
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<th>
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|
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
|
|
</th>
|
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</tr>
|
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</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/X/169?start=-3&limit=10&highlight=169">
|
|
Xp11.4
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Ornithine transcarbamylase deficiency
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/311250"> 311250 </a>
|
|
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="X-linked">XL</abbr>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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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">
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p>Ornithine carbamoyltransferase (<a href="https://enzyme.expasy.org/EC/2.1.3.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 2.1.3.3</a>) is a nuclear-encoded mitochondrial matrix enzyme that catalyzes the second step of the urea cycle in mammals.</p>
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Using rat liver OTC mRNA, <a href="#24" class="mim-tip-reference" title="Horwich, A. L., Kraus, J. P., Williams, K., Kalousek, F., Konigsberg, W., Rosenberg, L. E. <strong>Molecular cloning of the cDNA coding for rat ornithine transcarbamoylase.</strong> Proc. Nat. Acad. Sci. 80: 4258-4262, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6576335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6576335</a>] [<a href="https://doi.org/10.1073/pnas.80.14.4258" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6576335">Horwich et al. (1983)</a> isolated and characterized a cDNA corresponding to the OTC gene. The translated polypeptide has a molecular mass of 40 kD, but the authors noted that the mature, active enzyme is a trimer of identical 36-kD subunits, indicating posttranslational modification. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6576335" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Human Gene</em></strong></p><p>
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<a href="#21" class="mim-tip-reference" title="Horwich, A. L., Fenton, W. A., Williams, K. R., Kalousek, F., Kraus, J. P., Doolittle, R. F., Konigsberg, W., Rosenberg, L. E. <strong>Structure and expression of a complementary DNA for the nuclear coded precursor of human mitochondrial ornithine transcarbamylase.</strong> Science 224: 1068-1074, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6372096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6372096</a>] [<a href="https://doi.org/10.1126/science.6372096" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6372096">Horwich et al. (1984)</a> determined that the human OTC gene encodes a 354-amino acid protein which is synthesized on free cytoplasmic polyribosomes as a precursor of about 40 kD. This pre-OTC has an NH2-extension which is cleaved proteolytically concomitant with its posttranslational energy-dependent import into mitochondria. The OTC enzyme is synthesized in the cytoplasm and is directed to mitochondria by a 32-residue amino-terminal leader peptide. The protein sequence resembles that of both OTC and aspartate transcarbamylase from E. coli (see also <a href="#23" class="mim-tip-reference" title="Horwich, A. L., Kalousek, F., Mellman, I., Rosenberg, L. E. <strong>A leader peptide is sufficient to direct mitochondrial import of a chimeric protein.</strong> EMBO J. 4: 1129-1135, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3891325/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3891325</a>] [<a href="https://doi.org/10.1002/j.1460-2075.1985.tb03750.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3891325">Horwich et al., 1985</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3891325+6372096" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To define the critical residues and/or regions in the OTC leader peptide, <a href="#22" class="mim-tip-reference" title="Horwich, A. L., Kalousek, F., Fenton, W. A., Pollock, R. A., Rosenberg, L. E. <strong>Targeting of pre-ornithine transcarbamylase to mitochondria: definition of critical regions and residues in the leader peptide.</strong> Cell 44: 451-459, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3943133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3943133</a>] [<a href="https://doi.org/10.1016/0092-8674(86)90466-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3943133">Horwich et al. (1986)</a> synthesized OTC precursors with alterations in the leader portion. Analysis of deletions revealed that the mid-portion of the 32-residue leader peptide is an absolute requirement for both mitochondrial uptake and proteolytic processing. Further analysis of precursors with single substitutions revealed complete loss of function when arginine 23 was substituted with glycine. The critical role of this arginine residue may be mediated by participation in a local secondary structure, very likely an alpha-helix. In a review of the subject, <a href="#25" class="mim-tip-reference" title="Hurt, E. C., van Loon, A. P. G. M. <strong>How proteins find mitochondria and intramitochondrial compartments.</strong> Trends Biochem. Sci. 11: 204-207, 1986."None>Hurt and van Loon (1986)</a> presented evidence that the amino-terminal presequences also contain information for 'intramitochondrial sorting.' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3943133" 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="#48" class="mim-tip-reference" title="Tuchman, M., Matsuda, I., Munnich, A., Malcolm, S., Strautnieks, S., Briede, T. <strong>Proportions of spontaneous mutations in males and females with ornithine transcarbamylase deficiency.</strong> Am. J. Med. Genet. 55: 67-70, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7702100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7702100</a>] [<a href="https://doi.org/10.1002/ajmg.1320550118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7702100">Tuchman et al. (1995)</a> noted that the subunits of the human OTC homotrimer show 46% amino acid sequence homology to the catalytic subunit of E. coli aspartate transcarbamylase. Secondary structure predictions, distributions of hydrophilic and hydrophobic regions, and the pattern of conserved residues suggest that the 3-dimensional structures of the 2 proteins are likely to be similar. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7702100" 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="#30" class="mim-tip-reference" title="Li, L., Mao, Y., Zhao, L., Li, L., Wu, J., Zhao, M., Du, W., Yu, L., Jiang, P. <strong>p53 regulation of ammonia metabolism through urea cycle controls polyamine biosynthesis.</strong> Nature 567: 253-256, 2019. Note: Erratum: Nature 569: E10, 2019. Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30842655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30842655</a>] [<a href="https://doi.org/10.1038/s41586-019-0996-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30842655">Li et al. (2019)</a> reported that the tumor suppressor p53 (<a href="/entry/191170">191170</a>) regulates ammonia metabolism by repressing the urea cycle. Through transcriptional downregulation of CPS1 (<a href="/entry/608307">608307</a>), OTC, and ARG1 (<a href="/entry/608313">608313</a>), p53 suppresses ureagenesis and elimination of ammonia in vitro and in vivo, leading to the inhibition of tumor growth. Conversely, downregulation of these genes reciprocally activates p53 by MDM2 (<a href="/entry/164785">164785</a>)-mediated mechanism(s). Furthermore, the accumulation of ammonia causes a significant decline in mRNA translation of the polyamine biosynthetic rate-limiting enzyme ODC (ODC1; <a href="/entry/165640">165640</a>), thereby inhibiting the biosynthesis of polyamine and cell proliferation. <a href="#30" class="mim-tip-reference" title="Li, L., Mao, Y., Zhao, L., Li, L., Wu, J., Zhao, M., Du, W., Yu, L., Jiang, P. <strong>p53 regulation of ammonia metabolism through urea cycle controls polyamine biosynthesis.</strong> Nature 567: 253-256, 2019. Note: Erratum: Nature 569: E10, 2019. Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30842655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30842655</a>] [<a href="https://doi.org/10.1038/s41586-019-0996-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30842655">Li et al. (2019)</a> conclude that together, their findings linked p53 to ureagenesis and ammonia metabolism, and further revealed a role for ammonia in controlling polyamine biosynthesis and cell proliferation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30842655" 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>Hata et al. (<a href="#17" class="mim-tip-reference" title="Hata, A., Tsuzuki, T., Shimada, K., Takiguchi, M., Mori, M., Matsuda, I. <strong>Isolation and characterization of the human ornithine transcarbamylase gene: structure of the 5-prime-end region.</strong> J. Biochem. 100: 717-725, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3782067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3782067</a>] [<a href="https://doi.org/10.1093/oxfordjournals.jbchem.a121764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3782067">1986</a>, <a href="#18" class="mim-tip-reference" title="Hata, A., Tsuzuki, T., Shimada, K., Takiguchi, M., Mori, M., Matsuda, I. <strong>Structure of the human ornithine transcarbamylase gene.</strong> J. Biochem. 103: 302-308, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2836378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2836378</a>] [<a href="https://doi.org/10.1093/oxfordjournals.jbchem.a122265" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2836378">1988</a>) determined that the human OTC gene contains 10 exons and spans approximately 73 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3782067+2836378" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By in situ hybridization using DNA complementary to the human OTC gene, <a href="#31" class="mim-tip-reference" title="Lindgren, V., de Martinville, B., Horwich, A. L., Rosenberg, L. E., Francke, U. <strong>Human ornithine transcarbamylase locus mapped to band Xp21.1 near Duchenne muscular dystrophy locus.</strong> Science 226: 698-700, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6494904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6494904</a>] [<a href="https://doi.org/10.1126/science.6494904" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6494904">Lindgren et al. (1984)</a> mapped the gene to Xp21.1. Studies of the chromosomes of a female with Duchenne muscular hypertrophy and t(X;9)(p21;p22) indicated that OTC is proximal to DMD on Xp; the derivative chromosome 9 showed no hybridization with the OTC probe. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6494904" 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="#43" class="mim-tip-reference" title="Rozen, R., Fox, J., Fenton, W. A., Horwich, A. L., Rosenberg, L. E. <strong>Gene deletion and restriction fragment length polymorphisms at the human ornithine transcarbamylase locus.</strong> Nature 313: 815-817, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2983225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2983225</a>] [<a href="https://doi.org/10.1038/313815a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2983225">Rozen et al. (1985)</a> gave the first reported example of an OTC gene deletion that could be identified cytogenetically in a patient with OTC deficiency (<a href="/entry/311250">311250</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2983225" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a boy with a mild form of OTC deficiency, <a href="#34" class="mim-tip-reference" title="Maddalena, A., Sosnoski, D. M., Berry, G. T., Nussbaum, R. L. <strong>Mosaicism for an intragenic deletion in a boy with mild ornithine transcarbamylase deficiency.</strong> New Eng. J. Med. 319: 999-1003, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2843770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2843770</a>] [<a href="https://doi.org/10.1056/NEJM198810133191507" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2843770">Maddalena et al. (1988)</a> found somatic mosaicism for an intragenic deletion of the OTC gene (<a href="#0001">300461.0001</a>). In 3 of 24 unrelated patients with OTC deficiency, <a href="#35" class="mim-tip-reference" title="Maddalena, A., Spence, J. E., O'Brien, W. E., Nussbaum, R. L. <strong>Characterization of point mutations in the same arginine codon in three unrelated patients with ornithine transcarbamylase deficiency.</strong> J. Clin. Invest. 82: 1353-1358, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3170748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3170748</a>] [<a href="https://doi.org/10.1172/JCI113738" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3170748">Maddalena et al. (1988)</a> identified 2 different point mutations in the same codon of the OTC gene (<a href="#0002">300461.0002</a>-<a href="#0003">300461.0003</a>). The patients included 2 males with severe neonatal onset and a female patient with mild disease. Using the method of chemical mismatch cleavage developed by <a href="#4" class="mim-tip-reference" title="Cotton, R. G. H., Rodrigues, N. R., Campbell, R. D. <strong>Reactivity of cytosine and thymine in single-base-pair mismatches with hydroxylamine and osmium tetroxide and its application to the study of mutations.</strong> Proc. Nat. Acad. Sci. 85: 4397-4401, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3260032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3260032</a>] [<a href="https://doi.org/10.1073/pnas.85.12.4397" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3260032">Cotton et al. (1988)</a>, <a href="#14" class="mim-tip-reference" title="Grompe, M., Muzny, D. M., Caskey, C. T. <strong>Scanning detections of mutations in human ornithine transcarbamylase deficiency (OTC) by chemical mismatch cleavage. (Abstract)</strong> Am. J. Hum. Genet. 45 (suppl.): A192, 1989."None>Grompe et al. (1989)</a> identified 4 mutations and a polymorphism in the OTC gene (<a href="#0004">300461.0004</a>-<a href="#0009">300461.0009</a>) in 5 unrelated patients with OTC deficiency. <a href="#13" class="mim-tip-reference" title="Grompe, M., Caskey, C. T., Fenwick, R. G. <strong>Improved molecular diagnostics for ornithine transcarbamylase deficiency.</strong> Am. J. Hum. Genet. 48: 212-222, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1671317/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1671317</a>]" pmid="1671317">Grompe et al. (1991)</a> reported further on the use of chemical mismatch cleavage. Primers for specific amplification of OTC exons 1, 3, 5, 9, and 10 were also used to detect alterations in TaqI sites in exons 1, 3, 5, and 9. With a combination of molecular techniques, accurate diagnostic evaluation was possible in 17 of 18 families. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3260032+2843770+3170748+1671317" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a catalog of mutations in the OTC gene, <a href="#52" class="mim-tip-reference" title="Tuchman, M. <strong>Mutations and polymorphisms in the human ornithine transcarbamylase gene.</strong> Hum. Mutat. 2: 174-178, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8364586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8364586</a>] [<a href="https://doi.org/10.1002/humu.1380020304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8364586">Tuchman (1993)</a> reported deletions of variable size involving one or more exons, 29 different missense, nonsense, or frameshift mutations, and 3 polymorphisms in patients with OTC deficiency. Approximately 10 to 15% of all molecular alterations associated with OTC deficiency were large deletions involving all or part of the OTC gene. Most of the remaining mutations were unique to the affected family. Two mutations had been found in the sequence of the 'leader' peptide, 23 in the coding sequence of the 'mature' enzyme, and 4 in splicing recognition sites. <a href="#49" class="mim-tip-reference" title="Tuchman, M., Morizono, H., Reish, O., Yuan, X., Allewell, N. M. <strong>The molecular basis of ornithine transcarbamylase deficiency: modelling the human enzyme and the effects of mutations.</strong> J. Med. Genet. 32: 680-688, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8544185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8544185</a>] [<a href="https://doi.org/10.1136/jmg.32.9.680" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8544185">Tuchman et al. (1995)</a> tabulated 40 known mutations in the OTC gene resulting in enzyme deficiency, and described the predicted effects of all known mutations and deletions on the structure and function of the mature enzyme. Mutations in the OTC gene found in patients with hyperammonemia of the 'neonatal type' were clustered in important structural or functional domains, either in the interior of the protein, at the active site, or at the interchain interface, while mutations found in patients with milder 'late onset' disease were located primarily on the surface of the protein. <a href="#50" class="mim-tip-reference" title="Tuchman, M., Plante, R. J., Garcia-Perez, M. A., Rubio, V. <strong>Relative frequency of mutations causing ornithine transcarbamylase deficiency in 78 families.</strong> Hum. Genet. 97: 274-276, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8786061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8786061</a>] [<a href="https://doi.org/10.1007/BF02185751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8786061">Tuchman et al. (1996)</a> estimated that approximately 90 different mutations associated with OTC deficiency had been defined. Large deletions of 1 or more exons were found in 8% of 78 affected families, small deletions or insertions of 1 to 5 bases were found in approximately 10% of affected families, and splice site mutations were found in 18% of families. Contrary to previous reports, recurrent point mutations seemed to be equally distributed among most CpG dinucleotides rather than showing prevalent mutations. No single point mutation had a relative frequency of more than 6.4%. Of the 64 families with nucleotide substitutions, 24 (38%) were G to A with the next most common being C to T (16%) and A to T (11%). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8544185+8364586+8786061" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Gilbert-Dussardier, B., Segues, B., Rozet, J.-M., Rabier, D., Calvas, P., de Lumley, L., Bonnefond, J.-P., Munnich, A. <strong>Partial duplication [dup. TCAC (178)] and novel point mutations (T125M, G188R, A209V, and H302L) of the ornithine transcarbamylase gene in congenital hyperammonemia.</strong> Hum. Mutat. 8: 74-76, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8807340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8807340</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1996)8:1<74::AID-HUMU11>3.0.CO;2-O" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8807340">Gilbert-Dussardier et al. (1996)</a> described the first example of partial duplication of the OTC gene and 4 novel point mutations of this gene in patients with congenital hyperammonemia. <a href="#41" class="mim-tip-reference" title="Oppliger Leibundgut, E., Wermuth, B., Colombo, J.-P., Liechti-Gallati, S. <strong>Ornithine transcarbamylase deficiency: characterization of gene mutations and polymorphisms.</strong> Hum. Mutat. 8: 333-339, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8956038/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8956038</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1996)8:4<333::AID-HUMU6>3.0.CO;2-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8956038">Oppliger Leibundgut et al. (1996)</a> identified 3 new and 3 known mutations in male patients with OTC deficiency and studied the frequency of 4 polymorphisms of the OTC gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8807340+8956038" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 48 patients with OTC deficiency, <a href="#11" class="mim-tip-reference" title="Genet, S., Cranston, T., Middleton-Price, H. R. <strong>Mutation detection in 65 families with a possible diagnosis of ornithine carbamoyltransferase deficiency including 14 novel mutations.</strong> J. Inherit. Metab. Dis. 23: 669-676, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11117428/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11117428</a>] [<a href="https://doi.org/10.1023/a:1005614409241" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11117428">Genet et al. (2000)</a> identified mutations in the OTC gene. Fourteen of the mutations were previously unreported. Of the 48 identified mutations, 8 were large deletions, 8 were nonsense mutations, 26 were missense mutations, 4 were splice site mutations, and 2 were small deletions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11117428" 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="#47" class="mim-tip-reference" title="Tuchman, M., Jaleel, N., Morizono, H., Sheehy, L., Lynch, M. G. <strong>Mutations and polymorphisms in the human ornithine transcarbamylase gene.</strong> Hum. Mutat. 19: 93-107, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11793468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11793468</a>] [<a href="https://doi.org/10.1002/humu.10035" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11793468">Tuchman et al. (2002)</a> provided a comprehensive compilation of 244 mutations, including 13 polymorphisms in the OTC gene; 24 of the mutations were reported for the first time. Acute neonatal hyperammonemia was the presenting phenotype in 42% of the disease-causing mutations; 21% were found in patients with late-onset disease and approximately 37% were found in manifesting heterozygous females, most of which were presumed to confer a neonatal phenotype in hemizygous males. The authors found that most mutations in the OTC gene are 'private' and are distributed throughout the gene with paucity of mutation in the sequence encoding the leader peptide (exon 1 and beginning of exon 2) and in exon 7. Almost all mutations in consensus splicing sites conferred a neonatal phenotype. Several of the 13 polymorphisms are useful for allele tracking in patients in whom the mutation cannot be found. Even with sequencing of the entire reading frame and exon/intron boundaries, only about 80% of the mutations are detected in patients with proven OTC deficiency. The remaining probably occur within the introns or in regulatory domains. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11793468" 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="#55" class="mim-tip-reference" title="Yamaguchi, S., Brailey, L. L., Morizono, H., Bale, A. E., Tuchman, M. <strong>Mutations and polymorphisms in the human ornithine transcarbamylase (OTC) gene.</strong> Hum. Mutat. 27: 626-632, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16786505/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16786505</a>] [<a href="https://doi.org/10.1002/humu.20339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16786505">Yamaguchi et al. (2006)</a> gave an update on the mutations found in the OTC gene: 341 mutations, of which 93 had not been previously reported, and an additional 29 nondisease-causing mutations and polymorphisms. Of the 341 mutations, 149 were associated with neonatal onset of hyperammonemia (within the first week of life), 70 were seen in male patients with later onset of hyperammonemia, and 121 were found in heterozygous females. Most mutations in the OTC gene were specific to a particular family ('private' mutations). They were distributed throughout the gene, with a significant paucity of mutations in the 32 first codons encoding the 'leader' peptide (exon 1 and the beginning of exon 2). Almost all mutations in consensus splice sites conferred a neonatal-onset phenotype. Molecular screening methods identified mutations in about 80% of patients. <a href="#55" class="mim-tip-reference" title="Yamaguchi, S., Brailey, L. L., Morizono, H., Bale, A. E., Tuchman, M. <strong>Mutations and polymorphisms in the human ornithine transcarbamylase (OTC) gene.</strong> Hum. Mutat. 27: 626-632, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16786505/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16786505</a>] [<a href="https://doi.org/10.1002/humu.20339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16786505">Yamaguchi et al. (2006)</a> suggested that the remaining patients may have mutations in regulatory domains or mutations deep in the introns, which constitute 98.5% of the genomic sequence. In addition, a phenocopy of OTC deficiency caused by mutations in another unknown gene could not be excluded. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16786505" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#33" class="mim-tip-reference" title="Lopes-Marques, M., Pacheco, A. R., Peixoto, M. J., Cardoso, A. R., Serrano, C., Amorim, A., Prata, M. J., Cooper, D. N., Azevedo, L. <strong>Common polymorphic OTC variants can act as genetic modifiers of enzymatic activity.</strong> Hum. Mutat. 42: 978-989, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34015158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34015158</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34015158[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.24221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34015158">Lopes-Marques et al. (2021)</a> evaluated the role of 2 polymorphisms in the OTC gene, K46R and Q270R, on the function of wildtype OTC and OTC with the known pathogenic mutation R40H (<a href="#0029">300461.0029</a>) in HEK293 cells. The combination of both polymorphisms resulted in a significant increase in OTC enzyme function, whereas only the Q270R polymorphism resulted in a significant increase in OTC enzyme activity in cis with the R40H mutation. Structural analysis suggested that the Q270R polymorphism stabilized OTC with the R40H mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34015158" 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="#32" class="mim-tip-reference" title="Lo, R. S., Cromie, G. A., Tang, M., Teng, K., Owens, K., Sirr, A., Kutz, J. N., Morizono, H., Caldovic, L., Ah Mew, N., Gropman, A., Dudley, A. M. <strong>The functional impact of 1,570 individual amino acid substitutions in human OTC.</strong> Am. J. Hum. Genet. 110: 863-879, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37146589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37146589</a>] [<a href="https://doi.org/10.1016/j.ajhg.2023.03.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37146589">Lo et al. (2023)</a> developed a yeast growth-based assay to evaluate the function of OTC with each of 1,570 amino acid substitutions, which represented 84% of the missense mutations that were potentially caused by single nucleotide substitutions in the OTC gene. Residual growth values were used to categorize the mutations into functionally unimpaired (greater than 90% residual growth), functionally hypomorphic (5-90% residual growth), or functionally amorphic (less than 5% residual growth). Twenty-seven percent of the mutations were categorized as functionally amorphic. Correlations were identified between the residual growth values and disease severity, relative conservation, and functional gene regions. The exception to this was the 13-amino acid SMG loop of OTC, which appeared to be functionally relevant in human cells but not in yeast cells. <a href="#32" class="mim-tip-reference" title="Lo, R. S., Cromie, G. A., Tang, M., Teng, K., Owens, K., Sirr, A., Kutz, J. N., Morizono, H., Caldovic, L., Ah Mew, N., Gropman, A., Dudley, A. M. <strong>The functional impact of 1,570 individual amino acid substitutions in human OTC.</strong> Am. J. Hum. Genet. 110: 863-879, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37146589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37146589</a>] [<a href="https://doi.org/10.1016/j.ajhg.2023.03.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37146589">Lo et al. (2023)</a> suggested that this functional assay may help reclassification of pathogenicity of OTC variants, with effects on clinical actionability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37146589" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By screening conserved upstream regulatory regions of the OTC gene in 38 patients with a clinical diagnosis of ornithine transcarbamylase deficiency but without identifiable mutations in the OTC exons and exon/intron boundaries, <a href="#26" class="mim-tip-reference" title="Jang, Y. J., LaBella, A. L., Feeney, T. P., Braverman, N., Tuchman, M., Morizono, H., Ah Mew, N., Caldovic, L. <strong>Disease-causing mutations in the promoter and enhancer of the ornithine transcarbamylase gene.</strong> Hum. Mutat. 39: 527-536, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29282796/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29282796</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29282796[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.23394" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29282796">Jang et al. (2018)</a> identified mutations in 9 patients: 6 mutations in the OTC promoter (c.-106C-A, c.-115C-T, c.-116C-T, c.-106C-A, c.-115C-T, c.-116C-T) in patients 1-8 and 1 mutation in an OTC enhancer (c.-9384G-T) in patient 9. Using a dual luciferase assay to establish effects on gene expression, the authors found that all of the mutations resulted in reduction of luciferase activity. Pull-down assays showed that the c.-106C-A and c.-115C-T mutations affected HNF4 transcription factor binding. <a href="#26" class="mim-tip-reference" title="Jang, Y. J., LaBella, A. L., Feeney, T. P., Braverman, N., Tuchman, M., Morizono, H., Ah Mew, N., Caldovic, L. <strong>Disease-causing mutations in the promoter and enhancer of the ornithine transcarbamylase gene.</strong> Hum. Mutat. 39: 527-536, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29282796/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29282796</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29282796[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.23394" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29282796">Jang et al. (2018)</a> suggested that each of these mutations could be responsible for OTC deficiency in the patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29282796" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Origin of Mutations</em></strong></p><p>
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<a href="#48" class="mim-tip-reference" title="Tuchman, M., Matsuda, I., Munnich, A., Malcolm, S., Strautnieks, S., Briede, T. <strong>Proportions of spontaneous mutations in males and females with ornithine transcarbamylase deficiency.</strong> Am. J. Med. Genet. 55: 67-70, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7702100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7702100</a>] [<a href="https://doi.org/10.1002/ajmg.1320550118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7702100">Tuchman et al. (1995)</a> used specific mutation analysis to estimate the proportion of males and females with OTC deficiency whose mutations occurred in the germ cells of one of the parents. The mutations were identified in the probands, and subsequently carrier testing was performed on their mothers and some of the grandmothers. Of 28 OTC-deficient males, only 2 (7%) had sporadic mutations, whereas of 15 OTC-deficient females, 12 (80%) had sporadic mutations. Based on these results, <a href="#48" class="mim-tip-reference" title="Tuchman, M., Matsuda, I., Munnich, A., Malcolm, S., Strautnieks, S., Briede, T. <strong>Proportions of spontaneous mutations in males and females with ornithine transcarbamylase deficiency.</strong> Am. J. Med. Genet. 55: 67-70, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7702100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7702100</a>] [<a href="https://doi.org/10.1002/ajmg.1320550118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7702100">Tuchman et al. (1995)</a> estimated that the mutation rate in male germ cells is about 50-fold higher than in female germ cells. Assuming a fitness for males with OTC deficiency of 0.0 and the proportion of new female mutants as 0.80, the estimated fitness of heterozygous females is 0.4. Because of the difference in mutation rates between male and female germ cells, they suggested that nine-tenths or higher, rather than the conventional two-thirds proportion, be applied when estimating prior risk of carrier status in a mother of 1 affected male. The prior risk of a mother of an affected female is much lower, approximately two-tenths. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7702100" 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 13 unrelated girls with manifest OTC deficiency and their mothers, as well as 1 symptomatic and 3 asymptomatic adult females with proven carrier status, <a href="#40" class="mim-tip-reference" title="Oppliger Leibundgut, E., Liechti-Gallati, S., Colombo, J.-P., Wermuth, B. <strong>Ornithine transcarbamylase deficiency: ten new mutations and high proportion of de novo mutations in heterozygous females.</strong> Hum. Mutat. 9: 409-411, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9143919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9143919</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)9:5<409::AID-HUMU5>3.0.CO;2-Z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9143919">Oppliger Leibundgut et al. (1997)</a> identified 15 distinct single-base mutations, including 10 novel mutations. Sequence analysis of the DNA from the mothers of the 13 symptomatic girls revealed that only 1 of them was a carrier, thus confirming the high proportion of de novo mutations in heterozygous females. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9143919" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of families with OTC deficiency from the literature pooled with a French series, <a href="#1" class="mim-tip-reference" title="Bonaiti-Pellie, C., Pelet, A., Ogier, H., Nelson, J.-R., Largilliere, C., Berthelot, J., Saudubray, J.-M., Munnich, A. <strong>A probable sex difference in mutation rates in ornithine transcarbamylase deficiency.</strong> Hum. Genet. 84: 163-166, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2298452/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2298452</a>] [<a href="https://doi.org/10.1007/BF00208933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2298452">Bonaiti-Pellie et al. (1990)</a> concluded that segregation analysis provided no evidence for sporadic affected males, suggesting that there are virtually no mutations in eggs. They estimated that 57% of heterozygous females have the OTC gene on the basis of new mutations. The upper limit of the confidence interval, 16%, can be taken as the maximum prior probability that an affected male occurs as the result of a new mutation in his mother's germ cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2298452" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>X Inactivation</em></strong></p><p>
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To understand the correlation between X-inactivation status and the clinical phenotype of carrier females (which can vary from asymptomatic to severe hyperammonemia), <a href="#56" class="mim-tip-reference" title="Yorifuji, T., Muroi, J., Uematsu, A., Tanaka, K., Kiwaki, K., Endo, F., Matsuda, I., Nagasaka, H., Furusho, K. <strong>X-inactivation pattern in the liver of a manifesting female with ornithine transcarbamylase (OTC) deficiency.</strong> Clin. Genet. 54: 349-353, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9831349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9831349</a>] [<a href="https://doi.org/10.1034/j.1399-0004.1998.5440415.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9831349">Yorifuji et al. (1998)</a> analyzed the X-inactivation pattern of peripheral blood leukocytes in a family consisting of a clinically normal mother and 2 daughters with severe manifestation. In addition, they obtained tissue samples from various parts of the liver of one of the daughters and analyzed X-inactivation patterns and residual OTC activities. The X inactivation of peripheral blood leukocytes was nearly random in these carrier females and showed no correlation with the disease phenotype; however, the X inactivation of the liver was much more skewed and correlated well with the OTC activity of all samples. The degree of X inactivation varied considerably, even within the same liver. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9831349" 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>The trait 'sparse fur' (spf) in the mouse is due to OTC deficiency (<a href="#5" class="mim-tip-reference" title="DeMars, R., LeVan, S. L., Trend, B. L., Russell, L. B. <strong>Abnormal ornithine carbamyltransferase in mice having the sparse-fur mutation.</strong> Proc. Nat. Acad. Sci. 73: 1693-1697, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5727</a>] [<a href="https://doi.org/10.1073/pnas.73.5.1693" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5727">DeMars et al., 1976</a>). <a href="#53" class="mim-tip-reference" title="Veres, G., Gibbs, R. A., Scherer, S. E., Caskey, C. T. <strong>The molecular basis of the sparse fur mouse mutation.</strong> Science 237: 415-417, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3603027/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3603027</a>] [<a href="https://doi.org/10.1126/science.3603027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3603027">Veres et al. (1987)</a> demonstrated that the mutant OTC gene in the spf mouse contains a C-A transversion that alters a histidine residue to an asparagine residue at amino acid 117. The single base substitution in the cDNA for OTC from the mutant mouse was identified by means of a combination of 2 'new' techniques for rapid mutation analysis: ribonuclease A (RNase A) cleavage and the polymerase chain reaction (PCR) method for amplification of specific nucleotide sequences. The application of RNase A cleavage to localize the mutation, followed by PCR amplification of the mutated site, greatly simplified the procedure of mutation analysis (see also <a href="#38" class="mim-tip-reference" title="Ohtake, A., Takayanagi, M., Yamamoto, S., Kakinuma, H., Nakajima, H., Tatibana, M., Mori, M. <strong>Molecular basis of ornithine transcarbamylase deficiency in spf and spf-ash mutant mice.</strong> J. Inherit. Metab. Dis. 9: 289-291, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3099076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3099076</a>] [<a href="https://doi.org/10.1007/BF01799667" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3099076">Ohtake et al., 1986</a>). <a href="#54" class="mim-tip-reference" title="Wareham, K. A., Lyon, M. F., Glenister, P. H., Williams, E. D. <strong>Age related reactivation of an X-linked gene.</strong> Nature 327: 725-727, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3600770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3600770</a>] [<a href="https://doi.org/10.1038/327725a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3600770">Wareham et al. (1987)</a> used the OTC mutation in animals with the sparse fur trait (spf/Y or spf/spf) as a marker to demonstrate that there is an age-related reactivation of X-linked genes. They used mice with an X-autosome translocation that gives consistent nonrandom inactivation of the normal X. The normal X in these mice also carried a defective form of the histochemically demonstrable OTC enzyme. Only a small proportion of enzyme-positive cells was found in young animals. This proportion increased significantly with age, indicating a decrease in the stability of the X-inactivation mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3099076+3603027+3600770+5727" 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=300461[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<p><a href="#34" class="mim-tip-reference" title="Maddalena, A., Sosnoski, D. M., Berry, G. T., Nussbaum, R. L. <strong>Mosaicism for an intragenic deletion in a boy with mild ornithine transcarbamylase deficiency.</strong> New Eng. J. Med. 319: 999-1003, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2843770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2843770</a>] [<a href="https://doi.org/10.1056/NEJM198810133191507" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2843770">Maddalena et al. (1988)</a> found somatic mosaicism for an intragenic deletion of the OTC gene in a boy with mild OTC deficiency (<a href="/entry/311250">311250</a>) who had a history of only 1 hospitalization for hyperammonemia and no evidence of neurologic injury at 6 years of age. In a boy in whom mild OTC deficiency was first diagnosed at the age of 8 months, <a href="#29" class="mim-tip-reference" title="Legius, E., Baten, E., Stul, M., Marynen, P., Cassiman, J.-J. <strong>Sporadic late onset ornithine transcarbamylase deficiency in a boy with somatic mosaicism for an intragenic deletion.</strong> Clin. Genet. 38: 155-159, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2208768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2208768</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1990.tb03565.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2208768">Legius et al. (1990)</a> also found somatic mosaicism for a deletion in the OTC gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2208768+2843770" 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> rs68026851 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs68026851;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/rs68026851?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=rs68026851" 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=rs68026851" 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=RCV000011734 OR RCV000083434" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011734, RCV000083434" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011734...</a>
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<p>In 3 unrelated patients with OTC deficiency (<a href="/entry/311250">311250</a>), <a href="#35" class="mim-tip-reference" title="Maddalena, A., Spence, J. E., O'Brien, W. E., Nussbaum, R. L. <strong>Characterization of point mutations in the same arginine codon in three unrelated patients with ornithine transcarbamylase deficiency.</strong> J. Clin. Invest. 82: 1353-1358, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3170748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3170748</a>] [<a href="https://doi.org/10.1172/JCI113738" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3170748">Maddalena et al. (1988)</a> identified point mutations in the same arginine codon, number 109. Two unrelated males with neonatal onset of severe OTC deficiency had a G-A change, resulting in an arg109-to-gln (R109Q) substitution. In a third case, that of a symptomatic heterozygous female, a C-T transition converted residue 109 to a premature stop (R109X; <a href="#0003">300461.0003</a>). These results were interpreted as supporting the conclusion that TaqI restriction sites, which contain an internal CG, are particularly susceptible to C-T transition mutations due to deamination of a methylated C in either the sense or the antisense strand (the change in the antisense strand in the 2 males was a C-T transition.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3170748" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By assays in COS-1 cells containing the R109Q OTC mutation, <a href="#28" class="mim-tip-reference" title="Lee, J. T., Nussbaum, R. L. <strong>An arginine to glutamine mutation in residue 109 of human ornithine transcarbamylase completely abolishes enzymatic activity in COS1 cells.</strong> J. Clin. Invest. 84: 1762-1766, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2556444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2556444</a>] [<a href="https://doi.org/10.1172/JCI114360" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2556444">Lee and Nussbaum (1989)</a> showed that the specific activity of the mutant OTC was 100-fold lower than that of the wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2556444" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#44" class="mim-tip-reference" title="Strautnieks, S., Rutland, P., Malcolm, S. <strong>Arginine 109 to glutamine mutation in a girl with ornithine carbamoyl transferase deficiency.</strong> J. Med. Genet. 28: 871-874, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1757964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1757964</a>] [<a href="https://doi.org/10.1136/jmg.28.12.871" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1757964">Strautnieks et al. (1991)</a> identified the R109Q mutation in a female presenting at the age of 21 months with symptoms of OTC deficiency. The patient was identified by screening DNA from 29 families with at least one member with OTC deficiency. In 1 of 13 males with OTC deficiency, <a href="#45" class="mim-tip-reference" title="Suess, P. J., Tsai, M. Y., Holzknecht, R. A., Horowitz, M., Tuchman, M. <strong>Screening for gene deletions and known mutations in 13 patients with ornithine transcarbamylase deficiency.</strong> Biochem. Med. Metab. Biol. 47: 250-259, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1627356/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1627356</a>] [<a href="https://doi.org/10.1016/0885-4505(92)90033-u" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1627356">Suess et al. (1992)</a> identified the R109Q mutation. In addition, they found deletions in 3 of the 13 patients: one involving the entire gene, a second with deletion of exons 7 and 8, and a third with deletion of exon 9. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1757964+1627356" 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 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
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OTC, ARG109TER
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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> rs67960011 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs67960011;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/rs67960011?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=rs67960011" 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=rs67960011" 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=RCV000011735 OR RCV000083433" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011735, RCV000083433" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011735...</a>
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<p>See <a href="#35" class="mim-tip-reference" title="Maddalena, A., Spence, J. E., O'Brien, W. E., Nussbaum, R. L. <strong>Characterization of point mutations in the same arginine codon in three unrelated patients with ornithine transcarbamylase deficiency.</strong> J. Clin. Invest. 82: 1353-1358, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3170748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3170748</a>] [<a href="https://doi.org/10.1172/JCI113738" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3170748">Maddalena et al. (1988)</a> and <a href="#0002">300461.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3170748" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a female patient with mild OTC deficiency (<a href="/entry/311250">311250</a>), <a href="#16" class="mim-tip-reference" title="Hata, A., Setoyama, C., Shimada, K., Takeda, E., Kuroda, Y., Akaboshi, I., Matsuda, I. <strong>Ornithine transcarbamylase deficiency resulting from a C-to-T substitution in exon 5 of the ornithine transcarbamylase gene.</strong> Am. J. Hum. Genet. 45: 123-127, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2741942/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2741942</a>]" pmid="2741942">Hata et al. (1989)</a> demonstrated a C-T change in exon 5 of the OTC gene, resulting in a stop codon at residue 109 (arg109-to-ter; R109X). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2741942" 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="0004" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0004 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
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OTC, LEU111PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1800324 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1800324;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=rs1800324" 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=rs1800324" 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=RCV000011736" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011736" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011736</a>
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<p>In a patient with OTC deficiency (<a href="/entry/311250">311250</a>), <a href="#14" class="mim-tip-reference" title="Grompe, M., Muzny, D. M., Caskey, C. T. <strong>Scanning detections of mutations in human ornithine transcarbamylase deficiency (OTC) by chemical mismatch cleavage. (Abstract)</strong> Am. J. Hum. Genet. 45 (suppl.): A192, 1989."None>Grompe et al. (1989)</a> found a T-C mutation, resulting in a leu111-to-pro (L111P) change.</p>
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<a id="0005" class="mim-anchor"></a>
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<strong>.0005 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
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<span class="mim-text-font">
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OTC, GLN216GLU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs72558423 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs72558423;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=rs72558423" 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=rs72558423" 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=RCV000011737 OR RCV000083523" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011737, RCV000083523" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011737...</a>
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<span class="mim-text-font">
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<p>In a patient with OTC deficiency (<a href="/entry/311250">311250</a>), <a href="#14" class="mim-tip-reference" title="Grompe, M., Muzny, D. M., Caskey, C. T. <strong>Scanning detections of mutations in human ornithine transcarbamylase deficiency (OTC) by chemical mismatch cleavage. (Abstract)</strong> Am. J. Hum. Genet. 45 (suppl.): A192, 1989."None>Grompe et al. (1989)</a> found a C-G mutation, resulting in a gln216-to-glu (Q216E) change.</p>
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<a id="0006" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0006 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
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</span>
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</h4>
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OTC, GLU154TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs72556267 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs72556267;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=rs72556267" 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=rs72556267" 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=RCV000011738 OR RCV000083446" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011738, RCV000083446" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011738...</a>
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</span>
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<div>
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<span class="mim-text-font">
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<p>In a patient with OTC deficiency (<a href="/entry/311250">311250</a>), <a href="#14" class="mim-tip-reference" title="Grompe, M., Muzny, D. M., Caskey, C. T. <strong>Scanning detections of mutations in human ornithine transcarbamylase deficiency (OTC) by chemical mismatch cleavage. (Abstract)</strong> Am. J. Hum. Genet. 45 (suppl.): A192, 1989."None>Grompe et al. (1989)</a> identified a nonsense mutation, glu154-to-ter (E154X).</p>
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</span>
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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 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
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</span>
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</h4>
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OTC, LEU45PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs72554312 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs72554312;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=rs72554312" 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=rs72554312" 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=RCV000011739 OR RCV000083338" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011739, RCV000083338" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011739...</a>
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</span>
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<div>
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<span class="mim-text-font">
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<p>In a patient with OTC deficiency (<a href="/entry/311250">311250</a>), <a href="#14" class="mim-tip-reference" title="Grompe, M., Muzny, D. M., Caskey, C. T. <strong>Scanning detections of mutations in human ornithine transcarbamylase deficiency (OTC) by chemical mismatch cleavage. (Abstract)</strong> Am. J. Hum. Genet. 45 (suppl.): A192, 1989."None>Grompe et al. (1989)</a> concluded that the disorder was caused by a T-A change that converted leu45-to-pro (L45P). The patient also carried a lys46-to-arg polymorphism (K46R; <a href="#0009">300461.0009</a>).</p>
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</span>
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</div>
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<div>
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<div>
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<a id="0008" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0008 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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OTC, ARG26GLN
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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> rs68031618 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs68031618;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/rs68031618?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=rs68031618" 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=rs68031618" 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=RCV000011740 OR RCV000083565 OR RCV002408456" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011740, RCV000083565, RCV002408456" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011740...</a>
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<p>In a patient with OTC deficiency (<a href="/entry/311250">311250</a>), <a href="#14" class="mim-tip-reference" title="Grompe, M., Muzny, D. M., Caskey, C. T. <strong>Scanning detections of mutations in human ornithine transcarbamylase deficiency (OTC) by chemical mismatch cleavage. (Abstract)</strong> Am. J. Hum. Genet. 45 (suppl.): A192, 1989."None>Grompe et al. (1989)</a> found a G-A change, resulting in an arg26-to-gln (R26Q) change.</p>
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<strong>.0009 ORNITHINE TRANSCARBAMYLASE POLYMORPHISM</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> rs1800321 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1800321;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/rs1800321?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=rs1800321" 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=rs1800321" 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=RCV000011741 OR RCV000079082 OR RCV000268490 OR RCV001725114 OR RCV002311511" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011741, RCV000079082, RCV000268490, RCV001725114, RCV002311511" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011741...</a>
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<p>In a patient with OTC deficiency (<a href="/entry/311250">311250</a>) caused by mutation in codon 45 (leu45-to-pro; <a href="#0007">300461.0007</a>), <a href="#14" class="mim-tip-reference" title="Grompe, M., Muzny, D. M., Caskey, C. T. <strong>Scanning detections of mutations in human ornithine transcarbamylase deficiency (OTC) by chemical mismatch cleavage. (Abstract)</strong> Am. J. Hum. Genet. 45 (suppl.): A192, 1989."None>Grompe et al. (1989)</a> identified a lys46-to-arg (K46R) polymorphism in the OTC gene (see also <a href="#18" class="mim-tip-reference" title="Hata, A., Tsuzuki, T., Shimada, K., Takiguchi, M., Mori, M., Matsuda, I. <strong>Structure of the human ornithine transcarbamylase gene.</strong> J. Biochem. 103: 302-308, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2836378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2836378</a>] [<a href="https://doi.org/10.1093/oxfordjournals.jbchem.a122265" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2836378">Hata et al., 1988</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2836378" 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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<span class="mim-font">
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<strong>.0010 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
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OTC, ARG245TRP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs72558454 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs72558454;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=rs72558454" 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=rs72558454" 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=RCV000011746 OR RCV000083586" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011746, RCV000083586" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011746...</a>
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</span>
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<p>In a family with OTC deficiency (<a href="/entry/311250">311250</a>), <a href="#7" class="mim-tip-reference" title="Finkelstein, J. E., Francomano, C. A., Brusilow, S. W., Traystman, M. D. <strong>Use of denaturing gradient gel electrophoresis for detection of mutation and prospective diagnosis in late onset ornithine transcarbamylase deficiency.</strong> Genomics 7: 167-172, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2347583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2347583</a>] [<a href="https://doi.org/10.1016/0888-7543(90)90537-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2347583">Finkelstein et al. (1990)</a> identified a C-T change in the OTC gene, resulting in an arg245-to-trp (R245W) substitution. The patients showed some residual enzyme activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2347583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0011" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0011 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</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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OTC, IVS7DS, T-C, +2
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs72558431 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs72558431;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=rs72558431" 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=rs72558431" 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=RCV000011743 OR RCV000083544" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011743, RCV000083544" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011743...</a>
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</span>
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<span class="mim-text-font">
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<p>In a patient with severe OTC deficiency (<a href="/entry/311250">311250</a>), <a href="#3" class="mim-tip-reference" title="Carstens, R. P., Fenton, W. A., Rosenberg, L. R. <strong>Identification of RNA splicing errors resulting in human ornithine transcarbamylase deficiency.</strong> Am. J. Hum. Genet. 48: 1105-1114, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2035531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2035531</a>]" pmid="2035531">Carstens et al. (1991)</a> identified a C-T splice site mutation in the initial dinucleotide of intron 7 of the OTC gene, changing GT to GC and resulting in the skipping of exon 7 in the OTC cDNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2035531" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0012" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0012 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
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</h4>
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OTC, IVS7DS, A-G, +3
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs72558432 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs72558432;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=rs72558432" 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=rs72558432" 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=RCV000011744 OR RCV000083545" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011744, RCV000083545" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011744...</a>
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<p>In a patient with severe OTC deficiency (<a href="/entry/311250">311250</a>), <a href="#3" class="mim-tip-reference" title="Carstens, R. P., Fenton, W. A., Rosenberg, L. R. <strong>Identification of RNA splicing errors resulting in human ornithine transcarbamylase deficiency.</strong> Am. J. Hum. Genet. 48: 1105-1114, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2035531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2035531</a>]" pmid="2035531">Carstens et al. (1991)</a> identified a A-to-G splice site mutation in the third position of intron 7 of the OTC gene (GTA-GTG), resulting in skipping of exon 7 in the OTC cDNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2035531" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0013" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0013 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
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</span>
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</h4>
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OTC, IVS4, A-T, -2
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs66556380 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs66556380;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=rs66556380" 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=rs66556380" 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=RCV000011745 OR RCV000083419" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011745, RCV000083419" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011745...</a>
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<span class="mim-text-font">
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<p>In a case of severe OTC deficiency (<a href="/entry/311250">311250</a>), <a href="#3" class="mim-tip-reference" title="Carstens, R. P., Fenton, W. A., Rosenberg, L. R. <strong>Identification of RNA splicing errors resulting in human ornithine transcarbamylase deficiency.</strong> Am. J. Hum. Genet. 48: 1105-1114, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2035531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2035531</a>]" pmid="2035531">Carstens et al. (1991)</a> found an A-T change in the 3-prime splice acceptor AG dinucleotide at the end of intron 4, making this region an unacceptable splice junction. As a result, a cryptic 3-prime splice acceptor within exon 5 was used, producing a deletion of the first 12 bp of exon 5 and the resulting mRNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2035531" 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="0014" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0014 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
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</span>
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</h4>
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</div>
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OTC, ARG277TRP
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000011746 OR RCV000083586" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011746, RCV000083586" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011746...</a>
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<p>In 2 unrelated males with mild OTC deficiency (<a href="/entry/311250">311250</a>), <a href="#15" class="mim-tip-reference" title="Hata, A., Matsuura, T., Setoyama, C., Shimada, K., Yokoi, T., Akaboshi, I., Matsuda, I. <strong>A novel missense mutation in exon 8 of the ornithine transcarbamylase gene in two unrelated male patients with mild ornithine transcarbamylase deficiency.</strong> Hum. Genet. 87: 28-32, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2037279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2037279</a>] [<a href="https://doi.org/10.1007/BF01213087" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2037279">Hata et al. (1991)</a> identified a C-T change, resulting in an arg277-to-trp (R277W) substitution. In each family the affected male had an asymptomatic brother hemizygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2037279" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0015 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</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">rs67120076 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs67120076;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=rs67120076" 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=rs67120076" 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=RCV000011747 OR RCV000083536" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011747, RCV000083536" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011747...</a>
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<p><a href="#19" class="mim-tip-reference" title="Hentzen, D., Pelet, A., Feldman, D., Rabier, D., Berthelot, J., Munnich, A. <strong>Fatal hyperammonemia resulting from a C-to-T mutation at a MspI site of the ornithine transcarbamylase gene.</strong> Hum. Genet. 88: 153-156, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1721894/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1721894</a>] [<a href="https://doi.org/10.1007/BF00206063" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1721894">Hentzen et al. (1991)</a> described a family in which a proband and his maternal uncle and maternal great-uncle died in the neonatal period with hyperammonemia caused by OTC deficiency (<a href="/entry/311250">311250</a>). The mother and maternal grandmother of the proband showed a dramatic increment of urinary orotic acid following protein load, confirming their status as carriers. Using PCR amplification of OTC-specific mRNA derived from a postmortem biopsy of the liver of the proband, <a href="#19" class="mim-tip-reference" title="Hentzen, D., Pelet, A., Feldman, D., Rabier, D., Berthelot, J., Munnich, A. <strong>Fatal hyperammonemia resulting from a C-to-T mutation at a MspI site of the ornithine transcarbamylase gene.</strong> Hum. Genet. 88: 153-156, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1721894/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1721894</a>] [<a href="https://doi.org/10.1007/BF00206063" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1721894">Hentzen et al. (1991)</a> found that the MspI site (CCGG) in exon 7 was abolished. They identified a C-T transition in the OTC gene, resulting in a pro225-to-leu (P225L) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1721894" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0016 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
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OTC, GLU87LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs72554338 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs72554338;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=rs72554338" 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=rs72554338" 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=RCV000011748 OR RCV000083376" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011748, RCV000083376" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011748...</a>
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<p>In order to improve the efficiency of screening for mutant OTC genotypes in cases of OTC deficiency (<a href="/entry/311250">311250</a>), <a href="#6" class="mim-tip-reference" title="Feldmann, D., Rozet, J.-M., Pelet, A., Hentzen, D., Briand, P., Hubert, P., Largilliere, C., Rabier, D., Farriaux, J.-P., Munnich, A. <strong>Site specific screening for point mutations in ornithine transcarbamylase deficiency.</strong> J. Med. Genet. 29: 471-475, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1353535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1353535</a>]" pmid="1353535">Feldmann et al. (1992)</a> focused on the carbamyl phosphate-binding domain (encoded by the third exon) and the MspI restriction sites (CCGG) of the coding sequence (located in exons 2 and 7), as they contain mutation hotspots, i.e., CpG dinucleotides. Using this strategy, <a href="#6" class="mim-tip-reference" title="Feldmann, D., Rozet, J.-M., Pelet, A., Hentzen, D., Briand, P., Hubert, P., Largilliere, C., Rabier, D., Farriaux, J.-P., Munnich, A. <strong>Site specific screening for point mutations in ornithine transcarbamylase deficiency.</strong> J. Med. Genet. 29: 471-475, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1353535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1353535</a>]" pmid="1353535">Feldmann et al. (1992)</a> identified 3 'new' mutant genotypes. One of the new mutations was a glu87-lys (E87K) mutation found in a male baby who did well for the first 3.5 months of life, but thereafter lost his appetite and failed to thrive. Vomiting, agitation, abnormal movements, and generalized seizures occurred at 7.5 months of age, and he rapidly fell into a deep terminal coma with liver enlargement and hepatic failure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1353535" 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="0017" class="mim-anchor"></a>
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<strong>.0017 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
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OTC, GLY50TER
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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> rs67486158 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs67486158;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/rs67486158?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=rs67486158" 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=rs67486158" 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=RCV000011749 OR RCV000083346" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011749, RCV000083346" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011749...</a>
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<p><a href="#6" class="mim-tip-reference" title="Feldmann, D., Rozet, J.-M., Pelet, A., Hentzen, D., Briand, P., Hubert, P., Largilliere, C., Rabier, D., Farriaux, J.-P., Munnich, A. <strong>Site specific screening for point mutations in ornithine transcarbamylase deficiency.</strong> J. Med. Genet. 29: 471-475, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1353535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1353535</a>]" pmid="1353535">Feldmann et al. (1992)</a> found a gly50-to-ter (G50X) nonsense mutation in the OTC gene in a girl who was first admitted to hospital at the age of 8 months because of poor weight gain and vomiting. Hereditary fructose intolerance was first considered because of liver failure, but persistent hyperammonemia and increased urinary orotic acid led to the diagnosis of OTC deficiency (<a href="/entry/311250">311250</a>). Despite a low protein diet and arginine administration, the patient had repeated attacks of hyperammonemia. An orthotopic liver transplant was carried out at 5 years of age. Three years later the child was doing well on immunosuppressive agents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1353535" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0018" class="mim-anchor"></a>
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<h4>
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<strong>.0018 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
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OTC, GLY162ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs66626662 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs66626662;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=rs66626662" 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=rs66626662" 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=RCV000011750 OR RCV000083456" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011750, RCV000083456" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011750...</a>
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<p>In a male who died in deep coma at the age of 2 days, <a href="#6" class="mim-tip-reference" title="Feldmann, D., Rozet, J.-M., Pelet, A., Hentzen, D., Briand, P., Hubert, P., Largilliere, C., Rabier, D., Farriaux, J.-P., Munnich, A. <strong>Site specific screening for point mutations in ornithine transcarbamylase deficiency.</strong> J. Med. Genet. 29: 471-475, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1353535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1353535</a>]" pmid="1353535">Feldmann et al. (1992)</a> identified a glu162-to-arg (E162R) mutation, confirming OTC deficiency (<a href="/entry/311250">311250</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1353535" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0019 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
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OTC, 1-BP DEL, 403G
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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> rs72556255 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs72556255;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/rs72556255?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=rs72556255" 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=rs72556255" 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=RCV000011751 OR RCV000083425" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011751, RCV000083425" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011751...</a>
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<p>In a male with neonatal onset of hyperammonemia due to OTC deficiency (<a href="/entry/311250">311250</a>), <a href="#46" class="mim-tip-reference" title="Tuchman, M., Holzknecht, R. A., Gueron, A. B., Berry, S. A., Tsai, M. Y. <strong>Six new mutations in the ornithine transcarbamylase gene detected by single-strand conformational polymorphism.</strong> Pediat. Res. 32: 600-604, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1480464/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1480464</a>] [<a href="https://doi.org/10.1203/00006450-199211000-00024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1480464">Tuchman et al. (1992)</a> identified a 1-bp deletion in exon 5 of the OTC gene, a loss of guanine-403, causing a frameshift. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1480464" 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>.0020 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
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OTC, IVS2, 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">rs72554327 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs72554327;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=rs72554327" 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=rs72554327" 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=RCV000011752 OR RCV000083365" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011752, RCV000083365" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011752...</a>
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<p>In a male with neonatal onset of hyperammonemia caused by OTC deficiency (<a href="/entry/311250">311250</a>), <a href="#46" class="mim-tip-reference" title="Tuchman, M., Holzknecht, R. A., Gueron, A. B., Berry, S. A., Tsai, M. Y. <strong>Six new mutations in the ornithine transcarbamylase gene detected by single-strand conformational polymorphism.</strong> Pediat. Res. 32: 600-604, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1480464/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1480464</a>] [<a href="https://doi.org/10.1203/00006450-199211000-00024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1480464">Tuchman et al. (1992)</a> identified a G-A transition in the OTC gene at the 3-prime end of intron 2 involving nucleotide 217 (-1), resulting in an acceptor splicing site error. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1480464" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<span class="mim-font">
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<strong>.0021 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
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</h4>
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OTC, GLY47GLU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs72554331 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs72554331;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=rs72554331" 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=rs72554331" 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=RCV000011753 OR RCV000083369" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011753, RCV000083369" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011753...</a>
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</span>
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<span class="mim-text-font">
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<p>In a male with neonatal onset of hyperammonemia caused by OTC deficiency (<a href="/entry/311250">311250</a>), <a href="#46" class="mim-tip-reference" title="Tuchman, M., Holzknecht, R. A., Gueron, A. B., Berry, S. A., Tsai, M. Y. <strong>Six new mutations in the ornithine transcarbamylase gene detected by single-strand conformational polymorphism.</strong> Pediat. Res. 32: 600-604, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1480464/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1480464</a>] [<a href="https://doi.org/10.1203/00006450-199211000-00024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1480464">Tuchman et al. (1992)</a> identified a 236G-A transition in the OTC gene, resulting in a gly47-to-glu (G47E) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1480464" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0022" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0022 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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OTC, ARG62THR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs72554345 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs72554345;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=rs72554345" 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=rs72554345" 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=RCV000011754 OR RCV000083388" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011754, RCV000083388" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011754...</a>
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</span>
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</div>
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<span class="mim-text-font">
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<p>In a male in whom onset of clinical problems associated with OTC deficiency (<a href="/entry/311250">311250</a>) occurred after the neonatal period, <a href="#46" class="mim-tip-reference" title="Tuchman, M., Holzknecht, R. A., Gueron, A. B., Berry, S. A., Tsai, M. Y. <strong>Six new mutations in the ornithine transcarbamylase gene detected by single-strand conformational polymorphism.</strong> Pediat. Res. 32: 600-604, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1480464/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1480464</a>] [<a href="https://doi.org/10.1203/00006450-199211000-00024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1480464">Tuchman et al. (1992)</a> identified a 281G-C transversion in exon 3 of the OTC gene, resulting in an arg62-to-thr (R62T) substitution. This substitution changed the composition of the putative active site for carbamyl phosphate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1480464" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0023" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0023 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
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</span>
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</h4>
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</div>
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OTC, LEU272PHE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs72558465 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs72558465;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=rs72558465" 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=rs72558465" 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=RCV000011755 OR RCV000083607" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011755, RCV000083607" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011755...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a male in whom onset of clinical problems associated with OTC deficiency (<a href="/entry/311250">311250</a>) occurred after the neonatal period, <a href="#46" class="mim-tip-reference" title="Tuchman, M., Holzknecht, R. A., Gueron, A. B., Berry, S. A., Tsai, M. Y. <strong>Six new mutations in the ornithine transcarbamylase gene detected by single-strand conformational polymorphism.</strong> Pediat. Res. 32: 600-604, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1480464/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1480464</a>] [<a href="https://doi.org/10.1203/00006450-199211000-00024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1480464">Tuchman et al. (1992)</a> found a 912G-T transversion in exon 9 of the OTC gene, resulting in a leu272-to-phe (L272F) substitution. This changed a conserved domain of the gene, likely to be the ornithine binding site. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1480464" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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<div>
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<div>
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<a id="0024" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0024 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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OTC, TYR313ASP
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</div>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs66469337 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs66469337;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=rs66469337" 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=rs66469337" 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=RCV000011756 OR RCV000083325" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011756, RCV000083325" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011756...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a female with OTC deficiency (<a href="/entry/311250">311250</a>), <a href="#46" class="mim-tip-reference" title="Tuchman, M., Holzknecht, R. A., Gueron, A. B., Berry, S. A., Tsai, M. Y. <strong>Six new mutations in the ornithine transcarbamylase gene detected by single-strand conformational polymorphism.</strong> Pediat. Res. 32: 600-604, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1480464/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1480464</a>] [<a href="https://doi.org/10.1203/00006450-199211000-00024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1480464">Tuchman et al. (1992)</a> found a 1033T-G transversion in the OTC gene, resulting in a tyr313-to-asp (Y313D) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1480464" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<a id="0025" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0025 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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OTC, ARG129HIS
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs66656800 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs66656800;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=rs66656800" 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=rs66656800" 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=RCV000011757 OR RCV000083414" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011757, RCV000083414" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011757...</a>
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<p>In affected patients from 2 Spanish families with OTC deficiency (<a href="/entry/311250">311250</a>), <a href="#10" class="mim-tip-reference" title="Garcia-Perez, M. A., Sanjurjo, P., Rubio, V. <strong>Demonstration of the spf-ash mutation in Spanish patients with ornithine transcarbamylase deficiency of moderate severity.</strong> Hum. Genet. 95: 183-186, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7860064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7860064</a>] [<a href="https://doi.org/10.1007/BF00209398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7860064">Garcia-Perez et al. (1995)</a> identified an arg129-to-his (R129H) mutation in exon 4 of the OTC gene. The mutation results in the loss of a unique MspI restriction site that can be used for rapid diagnosis. The same mutation is found in the small spf-ash mouse, a rodent model of mild OTC deficiency, causing a neutral R129H mutation and inefficient splicing at the 5-prime donor site at the exon 4/intron 4 junction, with resultant 4 to 7% residual OTC activity. The mutation was found in the mother in one case, and arose de novo in the second case. Residual OTC activity, determined in a male and a female patient, was 1.3 and 3.5% of normal, respectively. Despite this low activity, the surviving patients had developed normally. One of them had reached reproductive age, raising the possibility of paternal transmission of the defect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7860064" 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>.0026 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</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">rs66741318 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs66741318;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=rs66741318" 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=rs66741318" 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=RCV000011758 OR RCV000083441" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011758, RCV000083441" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011758...</a>
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<p><a href="#27" class="mim-tip-reference" title="Komaki, S., Matsuura, T., Oyanagi, K., Hoshide, R., Kiwaki, K., Endo, F., Shimadzu, M., Matsuda, I. <strong>Familial lethal inheritance of a mutated paternal gene in females causing X-linked ornithine transcarbamylase (OTC) deficiency.</strong> Am. J. Med. Genet. 69: 177-181, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9056557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9056557</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19970317)69:2<177::aid-ajmg12>3.0.co;2-i" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9056557">Komaki et al. (1997)</a> identified a leu148-to-phe (L148F) substitution of the OTC gene in a 2-year-old girl with OTC deficiency (<a href="/entry/311250">311250</a>). OTC enzyme activity was 14% of control. Two elder sisters had died in childhood of hyperammonemia from OTC deficiency, and the patient also died of OTC deficiency. Enzyme activity in COS-1 cells transfected with the mutant cDNA was undetectable. Gene analysis showed that the mother had wildtype OTC alleles on both X chromosomes, and that the father was a mosaic for the mutant allele in his lymphocytes and spermatozoa. Thus, somatic and germline mosaicism led to the unusual pattern of X-linked inheritance in this family. <a href="#27" class="mim-tip-reference" title="Komaki, S., Matsuura, T., Oyanagi, K., Hoshide, R., Kiwaki, K., Endo, F., Shimadzu, M., Matsuda, I. <strong>Familial lethal inheritance of a mutated paternal gene in females causing X-linked ornithine transcarbamylase (OTC) deficiency.</strong> Am. J. Med. Genet. 69: 177-181, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9056557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9056557</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19970317)69:2<177::aid-ajmg12>3.0.co;2-i" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9056557">Komaki et al. (1997)</a> speculated about the possibility that skewed X inactivation, possibly due to inherited factors, was involved in this family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9056557" 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>.0027 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</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">rs72558412 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs72558412;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=rs72558412" 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=rs72558412" 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=RCV000011759 OR RCV000083513" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011759, RCV000083513" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011759...</a>
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<p><a href="#2" class="mim-tip-reference" title="Bowling, F., McGown, I., McGill, J., Cowley, D., Tuchman, M. <strong>Maternal gonadal mosaicism causing ornithine transcarbamylase deficiency.</strong> Am. J. Med. Genet. 85: 452-454, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10405441/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10405441</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19990827)85:5<452::aid-ajmg4>3.0.co;2-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10405441">Bowling et al. (1999)</a> reported a family with 2 consecutive males with OTC deficiency (<a href="/entry/311250">311250</a>), in which the mother had normal biochemical studies. OTC genotyping in both brothers showed a met206-to-arg (M206R) mutation in exon 6. Genotyping of the mother performed on peripheral blood leukocytes and skin fibroblasts showed no mutation, strongly suggesting gonadal mosaicism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10405441" 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>.0028 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</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> rs72554307 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs72554307;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/rs72554307?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=rs72554307" 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=rs72554307" 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=RCV000011760 OR RCV000083332" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011760, RCV000083332" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011760...</a>
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<p><a href="#42" class="mim-tip-reference" title="Ploechl, E., Ploechl, W., Stoeckler-Ipsiroglu, S., Pokorny, H., Wermuth, B. <strong>Late-onset ornithine transcarbamylase deficiency in two families with different mutations in the same codon.</strong> Clin. Genet. 59: 111-114, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11260212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11260212</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2001.590208.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11260212">Ploechl et al. (2001)</a> reported on late-onset OTC deficiency (<a href="/entry/311250">311250</a>) in 2 families with mutations in the same codon, but with different base substitutions. Onset of symptoms showed great variation, and clinical diagnosis was late and difficult. In family A, with a C-T transition causing an arg40-to-cys (R40C) substitution in the OTC gene, hemizygous males died at ages 12 and 18 years. In family B, with a G-A transition causing an arg40-to-his (R40H) substitution (<a href="#0029">300461.0029</a>), hemizygous males died at ages 20, 26, and 30 years. Whereas the R40C mutation is a private one, as in most cases of OTC deficiency, the R40H mutation is a recurrent one found first by <a href="#51" class="mim-tip-reference" title="Tuchman, M., Plante, R. J., McCann, M. T., Qureshi, A. A. <strong>Seven new mutations in the human ornithine transcarbamylase gene.</strong> Hum. Mutat. 4: 57-60, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7951259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7951259</a>] [<a href="https://doi.org/10.1002/humu.1380040109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7951259">Tuchman et al. (1994)</a>, and subsequently by <a href="#39" class="mim-tip-reference" title="Oppliger Leibundgut, E., Liechti-Gallati, S., Colombo, J. P., Wermuth, B. <strong>Ornithine transcarbamylase deficiency: new sites with increased probability of mutation.</strong> Hum. Genet. 95: 191-196, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7860066/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7860066</a>] [<a href="https://doi.org/10.1007/BF00209400" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7860066">Oppliger Leibundgut et al. (1995)</a> and <a href="#36" class="mim-tip-reference" title="Matsuda, I., Matsuura, T., Nishiyori, A., Komaki, S., Hoshide, R., Matsumoto, T., Funakoshi, M., Kiwaki, K., Endo, F., Hata, A., Shimadzu, M., Yoshino, M. <strong>Phenotypic variability in male patients carrying the mutant ornithine transcarbamylase (OTC) allele, arg40his, ranging from a child with an unfavourable prognosis to an asymptomatic older adult.</strong> J. Med. Genet. 33: 645-648, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8863155/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8863155</a>] [<a href="https://doi.org/10.1136/jmg.33.8.645" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8863155">Matsuda et al. (1996)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7860066+7951259+8863155+11260212" 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">rs72554308 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs72554308;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=rs72554308" 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=rs72554308" 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=RCV000011761 OR RCV000083333" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000011761, RCV000083333" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000011761...</a>
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<p>See <a href="#0028">300461.0028</a> and <a href="#42" class="mim-tip-reference" title="Ploechl, E., Ploechl, W., Stoeckler-Ipsiroglu, S., Pokorny, H., Wermuth, B. <strong>Late-onset ornithine transcarbamylase deficiency in two families with different mutations in the same codon.</strong> Clin. Genet. 59: 111-114, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11260212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11260212</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2001.590208.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11260212">Ploechl et al. (2001)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11260212" 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="#37" class="mim-tip-reference" title="Mavinakere, M., Morizono, H., Shi, D., Allewell, N. M., Tuchman, M. <strong>The clinically variable R40H mutant ornithine carbamoyltransferase shows cytosolic degradation of the precursor protein in CHO cells.</strong> J. Inherit. Metab. Dis. 24: 614-622, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11768581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11768581</a>] [<a href="https://doi.org/10.1023/a:1012726207870" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11768581">Mavinakere et al. (2001)</a> used (35)S labeling to study import and processing of OTC carrying the R40H mutation in intact CHO cells and in isolated rat liver mitochondria compared to wildtype and OTC carrying an R141Q mutant that causes complete enzyme deficiency. OTC protein carrying the R40H mutation seemed to be imported and processed by the mitochondria in a manner similar to that of wildtype. However, it was consistently degraded to a smaller fragment in the intact cells, unlike the wildtype and R141Q mutant. The mature form of the enzyme was not susceptible to degradation. <a href="#37" class="mim-tip-reference" title="Mavinakere, M., Morizono, H., Shi, D., Allewell, N. M., Tuchman, M. <strong>The clinically variable R40H mutant ornithine carbamoyltransferase shows cytosolic degradation of the precursor protein in CHO cells.</strong> J. Inherit. Metab. Dis. 24: 614-622, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11768581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11768581</a>] [<a href="https://doi.org/10.1023/a:1012726207870" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11768581">Mavinakere et al. (2001)</a> concluded that deficiency in OTC enzymatic function conferred by the R40H mutation is likely caused by enhanced degradation of the preprotein in the cytosol. The authors further proposed that the variation in the rate of OTC turnover is responsible for the heterogeneity of the clinical phenotype in patients carrying this mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11768581" 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="#Finkelstein1989" class="mim-tip-reference" title="Finkelstein, J. E., Hauser, E., Brusilow, S. W. <strong>Late onset ornithine transcarbamylase deficiency (OTCD) in males. (Abstract)</strong> Am. J. Hum. Genet. 45 (suppl.): A5, 1989.">Finkelstein et al. (1989)</a>; <a href="#Fox1986" class="mim-tip-reference" title="Fox, J. E., Hack, A. M., Fenton, W. A., Rosenberg, L. E. <strong>Identification and application of additional restriction fragment length polymorphisms at the human ornithine transcarbamylase locus.</strong> Am. J. Hum. Genet. 38: 841-847, 1986.">Fox et al. (1986)</a>; <a href="#Hoogenraad1983" class="mim-tip-reference" title="Hoogenraad, N., de Martinis, M. L., Danks, D. M. <strong>Immunological evidence for an ornithine transcarbamylase lesion resulting in the formation of enzyme with smaller protein subunits.</strong> J. Inherit. Metab. Dis. 6: 149-152, 1983.">Hoogenraad et al.
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[<a href="https://doi.org/10.1002/(sici)1096-8628(19990827)85:5<452::aid-ajmg4>3.0.co;2-4" target="_blank">Full Text</a>]
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Cotton, R. G. H., Rodrigues, N. R., Campbell, R. D.
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Proc. Nat. Acad. Sci. 85: 4397-4401, 1988.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3260032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3260032</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3260032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5727</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5727" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Finkelstein, J. E., Francomano, C. A., Brusilow, S. W., Traystman, M. D.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2347583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2347583</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2347583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Finkelstein, J. E., Hauser, E., Brusilow, S. W.
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<strong>Late onset ornithine transcarbamylase deficiency (OTCD) in males. (Abstract)</strong>
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Am. J. Hum. Genet. 45 (suppl.): A5, 1989.
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Fox, J. E., Hack, A. M., Fenton, W. A., Rosenberg, L. E.
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<strong>Identification and application of additional restriction fragment length polymorphisms at the human ornithine transcarbamylase locus.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3014867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3014867</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3014867" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7860064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7860064</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7860064" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/BF00209398" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11117428/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11117428</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11117428" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1023/a:1005614409241" target="_blank">Full Text</a>]
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<strong>Partial duplication [dup. TCAC (178)] and novel point mutations (T125M, G188R, A209V, and H302L) of the ornithine transcarbamylase gene in congenital hyperammonemia.</strong>
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Hum. Mutat. 8: 74-76, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8807340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8807340</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8807340" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(1996)8:1<74::AID-HUMU11>3.0.CO;2-O" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1671317/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1671317</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1671317" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Grompe, M., Muzny, D. M., Caskey, C. T.
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[<a href="https://doi.org/10.1007/BF01213087" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF02310869" target="_blank">Full Text</a>]
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<li>
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<a id="49" class="mim-anchor"></a>
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<a id="Tuchman1995" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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|
Tuchman, M., Morizono, H., Reish, O., Yuan, X., Allewell, N. M.
|
|
<strong>The molecular basis of ornithine transcarbamylase deficiency: modelling the human enzyme and the effects of mutations.</strong>
|
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J. Med. Genet. 32: 680-688, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8544185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8544185</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8544185" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.32.9.680" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="50" class="mim-anchor"></a>
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<a id="Tuchman1996" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
|
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Tuchman, M., Plante, R. J., Garcia-Perez, M. A., Rubio, V.
|
|
<strong>Relative frequency of mutations causing ornithine transcarbamylase deficiency in 78 families.</strong>
|
|
Hum. Genet. 97: 274-276, 1996.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8786061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8786061</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8786061" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/BF02185751" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="51" class="mim-anchor"></a>
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<a id="Tuchman1994" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tuchman, M., Plante, R. J., McCann, M. T., Qureshi, A. A.
|
|
<strong>Seven new mutations in the human ornithine transcarbamylase gene.</strong>
|
|
Hum. Mutat. 4: 57-60, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7951259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7951259</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7951259" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.1380040109" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="52" class="mim-anchor"></a>
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<a id="Tuchman1993" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tuchman, M.
|
|
<strong>Mutations and polymorphisms in the human ornithine transcarbamylase gene.</strong>
|
|
Hum. Mutat. 2: 174-178, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8364586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8364586</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8364586" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.1380020304" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="53" class="mim-anchor"></a>
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<a id="Veres1987" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Veres, G., Gibbs, R. A., Scherer, S. E., Caskey, C. T.
|
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<strong>The molecular basis of the sparse fur mouse mutation.</strong>
|
|
Science 237: 415-417, 1987.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3603027/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3603027</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3603027" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.3603027" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="54" class="mim-anchor"></a>
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<a id="Wareham1987" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wareham, K. A., Lyon, M. F., Glenister, P. H., Williams, E. D.
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<strong>Age related reactivation of an X-linked gene.</strong>
|
|
Nature 327: 725-727, 1987.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3600770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3600770</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3600770" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/327725a0" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="55" class="mim-anchor"></a>
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<a id="Yamaguchi2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yamaguchi, S., Brailey, L. L., Morizono, H., Bale, A. E., Tuchman, M.
|
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<strong>Mutations and polymorphisms in the human ornithine transcarbamylase (OTC) gene.</strong>
|
|
Hum. Mutat. 27: 626-632, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16786505/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16786505</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16786505" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.20339" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="56" class="mim-anchor"></a>
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<a id="Yorifuji1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yorifuji, T., Muroi, J., Uematsu, A., Tanaka, K., Kiwaki, K., Endo, F., Matsuda, I., Nagasaka, H., Furusho, K.
|
|
<strong>X-inactivation pattern in the liver of a manifesting female with ornithine transcarbamylase (OTC) deficiency.</strong>
|
|
Clin. Genet. 54: 349-353, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9831349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9831349</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9831349" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1034/j.1399-0004.1998.5440415.x" target="_blank">Full Text</a>]
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</ol>
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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="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 08/09/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 05/21/2019<br>Victor A. McKusick - updated : 10/13/2006
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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="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin : 11/26/2003
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</span>
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</div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 08/09/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 07/01/2019<br>alopez : 05/21/2019<br>alopez : 01/26/2017<br>alopez : 10/13/2006<br>carol : 6/3/2004<br>tkritzer : 12/11/2003<br>carol : 12/4/2003<br>ckniffin : 12/4/2003
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</span>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 300461
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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ORNITHINE CARBAMOYLTRANSFERASE; OTC
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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ORNITHINE TRANSCARBAMYLASE
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: OTC</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 80908008;
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<strong>ICD10CM:</strong> E72.4;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
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Cytogenetic location: Xp11.4
|
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|
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Genomic coordinates <span class="small">(GRCh38)</span> : X:38,327,684-38,422,928 </span>
|
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</em>
|
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</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
|
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</p>
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</div>
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<div>
|
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
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
|
|
</th>
|
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</tr>
|
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</thead>
|
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<tbody>
|
|
|
|
<tr>
|
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<td rowspan="1">
|
|
<span class="mim-font">
|
|
Xp11.4
|
|
</span>
|
|
</td>
|
|
|
|
|
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<td>
|
|
<span class="mim-font">
|
|
Ornithine transcarbamylase deficiency
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
311250
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
X-linked
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
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</tr>
|
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|
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|
|
</tbody>
|
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</table>
|
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</div>
|
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</div>
|
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<div>
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<br />
|
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
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</h4>
|
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Ornithine carbamoyltransferase (EC 2.1.3.3) is a nuclear-encoded mitochondrial matrix enzyme that catalyzes the second step of the urea cycle in mammals.</p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
<span class="mim-text-font">
|
|
<p><strong><em>Rat Gene</em></strong></p><p>
|
|
Using rat liver OTC mRNA, Horwich et al. (1983) isolated and characterized a cDNA corresponding to the OTC gene. The translated polypeptide has a molecular mass of 40 kD, but the authors noted that the mature, active enzyme is a trimer of identical 36-kD subunits, indicating posttranslational modification. </p><p><strong><em>Human Gene</em></strong></p><p>
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Horwich et al. (1984) determined that the human OTC gene encodes a 354-amino acid protein which is synthesized on free cytoplasmic polyribosomes as a precursor of about 40 kD. This pre-OTC has an NH2-extension which is cleaved proteolytically concomitant with its posttranslational energy-dependent import into mitochondria. The OTC enzyme is synthesized in the cytoplasm and is directed to mitochondria by a 32-residue amino-terminal leader peptide. The protein sequence resembles that of both OTC and aspartate transcarbamylase from E. coli (see also Horwich et al., 1985). </p><p>To define the critical residues and/or regions in the OTC leader peptide, Horwich et al. (1986) synthesized OTC precursors with alterations in the leader portion. Analysis of deletions revealed that the mid-portion of the 32-residue leader peptide is an absolute requirement for both mitochondrial uptake and proteolytic processing. Further analysis of precursors with single substitutions revealed complete loss of function when arginine 23 was substituted with glycine. The critical role of this arginine residue may be mediated by participation in a local secondary structure, very likely an alpha-helix. In a review of the subject, Hurt and van Loon (1986) presented evidence that the amino-terminal presequences also contain information for 'intramitochondrial sorting.' </p><p>Tuchman et al. (1995) noted that the subunits of the human OTC homotrimer show 46% amino acid sequence homology to the catalytic subunit of E. coli aspartate transcarbamylase. Secondary structure predictions, distributions of hydrophilic and hydrophobic regions, and the pattern of conserved residues suggest that the 3-dimensional structures of the 2 proteins are likely to be similar. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Li et al. (2019) reported that the tumor suppressor p53 (191170) regulates ammonia metabolism by repressing the urea cycle. Through transcriptional downregulation of CPS1 (608307), OTC, and ARG1 (608313), p53 suppresses ureagenesis and elimination of ammonia in vitro and in vivo, leading to the inhibition of tumor growth. Conversely, downregulation of these genes reciprocally activates p53 by MDM2 (164785)-mediated mechanism(s). Furthermore, the accumulation of ammonia causes a significant decline in mRNA translation of the polyamine biosynthetic rate-limiting enzyme ODC (ODC1; 165640), thereby inhibiting the biosynthesis of polyamine and cell proliferation. Li et al. (2019) conclude that together, their findings linked p53 to ureagenesis and ammonia metabolism, and further revealed a role for ammonia in controlling polyamine biosynthesis and cell proliferation. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Hata et al. (1986, 1988) determined that the human OTC gene contains 10 exons and spans approximately 73 kb. </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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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By in situ hybridization using DNA complementary to the human OTC gene, Lindgren et al. (1984) mapped the gene to Xp21.1. Studies of the chromosomes of a female with Duchenne muscular hypertrophy and t(X;9)(p21;p22) indicated that OTC is proximal to DMD on Xp; the derivative chromosome 9 showed no hybridization with the OTC probe. </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>
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</h4>
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<span class="mim-text-font">
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<p>Rozen et al. (1985) gave the first reported example of an OTC gene deletion that could be identified cytogenetically in a patient with OTC deficiency (311250). </p><p>In a boy with a mild form of OTC deficiency, Maddalena et al. (1988) found somatic mosaicism for an intragenic deletion of the OTC gene (300461.0001). In 3 of 24 unrelated patients with OTC deficiency, Maddalena et al. (1988) identified 2 different point mutations in the same codon of the OTC gene (300461.0002-300461.0003). The patients included 2 males with severe neonatal onset and a female patient with mild disease. Using the method of chemical mismatch cleavage developed by Cotton et al. (1988), Grompe et al. (1989) identified 4 mutations and a polymorphism in the OTC gene (300461.0004-300461.0009) in 5 unrelated patients with OTC deficiency. Grompe et al. (1991) reported further on the use of chemical mismatch cleavage. Primers for specific amplification of OTC exons 1, 3, 5, 9, and 10 were also used to detect alterations in TaqI sites in exons 1, 3, 5, and 9. With a combination of molecular techniques, accurate diagnostic evaluation was possible in 17 of 18 families. </p><p>In a catalog of mutations in the OTC gene, Tuchman (1993) reported deletions of variable size involving one or more exons, 29 different missense, nonsense, or frameshift mutations, and 3 polymorphisms in patients with OTC deficiency. Approximately 10 to 15% of all molecular alterations associated with OTC deficiency were large deletions involving all or part of the OTC gene. Most of the remaining mutations were unique to the affected family. Two mutations had been found in the sequence of the 'leader' peptide, 23 in the coding sequence of the 'mature' enzyme, and 4 in splicing recognition sites. Tuchman et al. (1995) tabulated 40 known mutations in the OTC gene resulting in enzyme deficiency, and described the predicted effects of all known mutations and deletions on the structure and function of the mature enzyme. Mutations in the OTC gene found in patients with hyperammonemia of the 'neonatal type' were clustered in important structural or functional domains, either in the interior of the protein, at the active site, or at the interchain interface, while mutations found in patients with milder 'late onset' disease were located primarily on the surface of the protein. Tuchman et al. (1996) estimated that approximately 90 different mutations associated with OTC deficiency had been defined. Large deletions of 1 or more exons were found in 8% of 78 affected families, small deletions or insertions of 1 to 5 bases were found in approximately 10% of affected families, and splice site mutations were found in 18% of families. Contrary to previous reports, recurrent point mutations seemed to be equally distributed among most CpG dinucleotides rather than showing prevalent mutations. No single point mutation had a relative frequency of more than 6.4%. Of the 64 families with nucleotide substitutions, 24 (38%) were G to A with the next most common being C to T (16%) and A to T (11%). </p><p>Gilbert-Dussardier et al. (1996) described the first example of partial duplication of the OTC gene and 4 novel point mutations of this gene in patients with congenital hyperammonemia. Oppliger Leibundgut et al. (1996) identified 3 new and 3 known mutations in male patients with OTC deficiency and studied the frequency of 4 polymorphisms of the OTC gene. </p><p>In 48 patients with OTC deficiency, Genet et al. (2000) identified mutations in the OTC gene. Fourteen of the mutations were previously unreported. Of the 48 identified mutations, 8 were large deletions, 8 were nonsense mutations, 26 were missense mutations, 4 were splice site mutations, and 2 were small deletions. </p><p>Tuchman et al. (2002) provided a comprehensive compilation of 244 mutations, including 13 polymorphisms in the OTC gene; 24 of the mutations were reported for the first time. Acute neonatal hyperammonemia was the presenting phenotype in 42% of the disease-causing mutations; 21% were found in patients with late-onset disease and approximately 37% were found in manifesting heterozygous females, most of which were presumed to confer a neonatal phenotype in hemizygous males. The authors found that most mutations in the OTC gene are 'private' and are distributed throughout the gene with paucity of mutation in the sequence encoding the leader peptide (exon 1 and beginning of exon 2) and in exon 7. Almost all mutations in consensus splicing sites conferred a neonatal phenotype. Several of the 13 polymorphisms are useful for allele tracking in patients in whom the mutation cannot be found. Even with sequencing of the entire reading frame and exon/intron boundaries, only about 80% of the mutations are detected in patients with proven OTC deficiency. The remaining probably occur within the introns or in regulatory domains. </p><p>Yamaguchi et al. (2006) gave an update on the mutations found in the OTC gene: 341 mutations, of which 93 had not been previously reported, and an additional 29 nondisease-causing mutations and polymorphisms. Of the 341 mutations, 149 were associated with neonatal onset of hyperammonemia (within the first week of life), 70 were seen in male patients with later onset of hyperammonemia, and 121 were found in heterozygous females. Most mutations in the OTC gene were specific to a particular family ('private' mutations). They were distributed throughout the gene, with a significant paucity of mutations in the 32 first codons encoding the 'leader' peptide (exon 1 and the beginning of exon 2). Almost all mutations in consensus splice sites conferred a neonatal-onset phenotype. Molecular screening methods identified mutations in about 80% of patients. Yamaguchi et al. (2006) suggested that the remaining patients may have mutations in regulatory domains or mutations deep in the introns, which constitute 98.5% of the genomic sequence. In addition, a phenocopy of OTC deficiency caused by mutations in another unknown gene could not be excluded. </p><p>Lopes-Marques et al. (2021) evaluated the role of 2 polymorphisms in the OTC gene, K46R and Q270R, on the function of wildtype OTC and OTC with the known pathogenic mutation R40H (300461.0029) in HEK293 cells. The combination of both polymorphisms resulted in a significant increase in OTC enzyme function, whereas only the Q270R polymorphism resulted in a significant increase in OTC enzyme activity in cis with the R40H mutation. Structural analysis suggested that the Q270R polymorphism stabilized OTC with the R40H mutation. </p><p>Lo et al. (2023) developed a yeast growth-based assay to evaluate the function of OTC with each of 1,570 amino acid substitutions, which represented 84% of the missense mutations that were potentially caused by single nucleotide substitutions in the OTC gene. Residual growth values were used to categorize the mutations into functionally unimpaired (greater than 90% residual growth), functionally hypomorphic (5-90% residual growth), or functionally amorphic (less than 5% residual growth). Twenty-seven percent of the mutations were categorized as functionally amorphic. Correlations were identified between the residual growth values and disease severity, relative conservation, and functional gene regions. The exception to this was the 13-amino acid SMG loop of OTC, which appeared to be functionally relevant in human cells but not in yeast cells. Lo et al. (2023) suggested that this functional assay may help reclassification of pathogenicity of OTC variants, with effects on clinical actionability. </p><p>By screening conserved upstream regulatory regions of the OTC gene in 38 patients with a clinical diagnosis of ornithine transcarbamylase deficiency but without identifiable mutations in the OTC exons and exon/intron boundaries, Jang et al. (2018) identified mutations in 9 patients: 6 mutations in the OTC promoter (c.-106C-A, c.-115C-T, c.-116C-T, c.-106C-A, c.-115C-T, c.-116C-T) in patients 1-8 and 1 mutation in an OTC enhancer (c.-9384G-T) in patient 9. Using a dual luciferase assay to establish effects on gene expression, the authors found that all of the mutations resulted in reduction of luciferase activity. Pull-down assays showed that the c.-106C-A and c.-115C-T mutations affected HNF4 transcription factor binding. Jang et al. (2018) suggested that each of these mutations could be responsible for OTC deficiency in the patients. </p><p><strong><em>Origin of Mutations</em></strong></p><p>
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Tuchman et al. (1995) used specific mutation analysis to estimate the proportion of males and females with OTC deficiency whose mutations occurred in the germ cells of one of the parents. The mutations were identified in the probands, and subsequently carrier testing was performed on their mothers and some of the grandmothers. Of 28 OTC-deficient males, only 2 (7%) had sporadic mutations, whereas of 15 OTC-deficient females, 12 (80%) had sporadic mutations. Based on these results, Tuchman et al. (1995) estimated that the mutation rate in male germ cells is about 50-fold higher than in female germ cells. Assuming a fitness for males with OTC deficiency of 0.0 and the proportion of new female mutants as 0.80, the estimated fitness of heterozygous females is 0.4. Because of the difference in mutation rates between male and female germ cells, they suggested that nine-tenths or higher, rather than the conventional two-thirds proportion, be applied when estimating prior risk of carrier status in a mother of 1 affected male. The prior risk of a mother of an affected female is much lower, approximately two-tenths. </p><p>Studying 13 unrelated girls with manifest OTC deficiency and their mothers, as well as 1 symptomatic and 3 asymptomatic adult females with proven carrier status, Oppliger Leibundgut et al. (1997) identified 15 distinct single-base mutations, including 10 novel mutations. Sequence analysis of the DNA from the mothers of the 13 symptomatic girls revealed that only 1 of them was a carrier, thus confirming the high proportion of de novo mutations in heterozygous females. </p><p>In a study of families with OTC deficiency from the literature pooled with a French series, Bonaiti-Pellie et al. (1990) concluded that segregation analysis provided no evidence for sporadic affected males, suggesting that there are virtually no mutations in eggs. They estimated that 57% of heterozygous females have the OTC gene on the basis of new mutations. The upper limit of the confidence interval, 16%, can be taken as the maximum prior probability that an affected male occurs as the result of a new mutation in his mother's germ cells. </p><p><strong><em>X Inactivation</em></strong></p><p>
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To understand the correlation between X-inactivation status and the clinical phenotype of carrier females (which can vary from asymptomatic to severe hyperammonemia), Yorifuji et al. (1998) analyzed the X-inactivation pattern of peripheral blood leukocytes in a family consisting of a clinically normal mother and 2 daughters with severe manifestation. In addition, they obtained tissue samples from various parts of the liver of one of the daughters and analyzed X-inactivation patterns and residual OTC activities. The X inactivation of peripheral blood leukocytes was nearly random in these carrier females and showed no correlation with the disease phenotype; however, the X inactivation of the liver was much more skewed and correlated well with the OTC activity of all samples. The degree of X inactivation varied considerably, even within the same liver. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The trait 'sparse fur' (spf) in the mouse is due to OTC deficiency (DeMars et al., 1976). Veres et al. (1987) demonstrated that the mutant OTC gene in the spf mouse contains a C-A transversion that alters a histidine residue to an asparagine residue at amino acid 117. The single base substitution in the cDNA for OTC from the mutant mouse was identified by means of a combination of 2 'new' techniques for rapid mutation analysis: ribonuclease A (RNase A) cleavage and the polymerase chain reaction (PCR) method for amplification of specific nucleotide sequences. The application of RNase A cleavage to localize the mutation, followed by PCR amplification of the mutated site, greatly simplified the procedure of mutation analysis (see also Ohtake et al., 1986). Wareham et al. (1987) used the OTC mutation in animals with the sparse fur trait (spf/Y or spf/spf) as a marker to demonstrate that there is an age-related reactivation of X-linked genes. They used mice with an X-autosome translocation that gives consistent nonrandom inactivation of the normal X. The normal X in these mice also carried a defective form of the histochemically demonstrable OTC enzyme. Only a small proportion of enzyme-positive cells was found in young animals. This proportion increased significantly with age, indicating a decrease in the stability of the X-inactivation mechanism. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>29 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</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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OTC, DEL
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<br />
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ClinVar: RCV000011733
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Maddalena et al. (1988) found somatic mosaicism for an intragenic deletion of the OTC gene in a boy with mild OTC deficiency (311250) who had a history of only 1 hospitalization for hyperammonemia and no evidence of neurologic injury at 6 years of age. In a boy in whom mild OTC deficiency was first diagnosed at the age of 8 months, Legius et al. (1990) also found somatic mosaicism for a deletion in the OTC gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0002 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</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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OTC, ARG109GLN
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<br />
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SNP: rs68026851,
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gnomAD: rs68026851,
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ClinVar: RCV000011734, RCV000083434
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 3 unrelated patients with OTC deficiency (311250), Maddalena et al. (1988) identified point mutations in the same arginine codon, number 109. Two unrelated males with neonatal onset of severe OTC deficiency had a G-A change, resulting in an arg109-to-gln (R109Q) substitution. In a third case, that of a symptomatic heterozygous female, a C-T transition converted residue 109 to a premature stop (R109X; 300461.0003). These results were interpreted as supporting the conclusion that TaqI restriction sites, which contain an internal CG, are particularly susceptible to C-T transition mutations due to deamination of a methylated C in either the sense or the antisense strand (the change in the antisense strand in the 2 males was a C-T transition.) </p><p>By assays in COS-1 cells containing the R109Q OTC mutation, Lee and Nussbaum (1989) showed that the specific activity of the mutant OTC was 100-fold lower than that of the wildtype. </p><p>Strautnieks et al. (1991) identified the R109Q mutation in a female presenting at the age of 21 months with symptoms of OTC deficiency. The patient was identified by screening DNA from 29 families with at least one member with OTC deficiency. In 1 of 13 males with OTC deficiency, Suess et al. (1992) identified the R109Q mutation. In addition, they found deletions in 3 of the 13 patients: one involving the entire gene, a second with deletion of exons 7 and 8, and a third with deletion of exon 9. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0003 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</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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OTC, ARG109TER
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<br />
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SNP: rs67960011,
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gnomAD: rs67960011,
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ClinVar: RCV000011735, RCV000083433
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>See Maddalena et al. (1988) and 300461.0002. </p><p>In a female patient with mild OTC deficiency (311250), Hata et al. (1989) demonstrated a C-T change in exon 5 of the OTC gene, resulting in a stop codon at residue 109 (arg109-to-ter; R109X). </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 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</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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OTC, LEU111PRO
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<br />
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|
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SNP: rs1800324,
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ClinVar: RCV000011736
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a patient with OTC deficiency (311250), Grompe et al. (1989) found a T-C mutation, resulting in a leu111-to-pro (L111P) change.</p>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0005 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</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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OTC, GLN216GLU
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<br />
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|
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SNP: rs72558423,
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ClinVar: RCV000011737, RCV000083523
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a patient with OTC deficiency (311250), Grompe et al. (1989) found a C-G mutation, resulting in a gln216-to-glu (Q216E) change.</p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0006 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
|
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OTC, GLU154TER
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<br />
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|
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SNP: rs72556267,
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ClinVar: RCV000011738, RCV000083446
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a patient with OTC deficiency (311250), Grompe et al. (1989) identified a nonsense mutation, glu154-to-ter (E154X).</p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
OTC, LEU45PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs72554312,
|
|
|
|
|
|
|
|
ClinVar: RCV000011739, RCV000083338
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with OTC deficiency (311250), Grompe et al. (1989) concluded that the disorder was caused by a T-A change that converted leu45-to-pro (L45P). The patient also carried a lys46-to-arg polymorphism (K46R; 300461.0009).</p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
OTC, ARG26GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs68031618,
|
|
|
|
|
|
gnomAD: rs68031618,
|
|
|
|
|
|
ClinVar: RCV000011740, RCV000083565, RCV002408456
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with OTC deficiency (311250), Grompe et al. (1989) found a G-A change, resulting in an arg26-to-gln (R26Q) change.</p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 ORNITHINE TRANSCARBAMYLASE POLYMORPHISM</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
OTC, LYS46ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1800321,
|
|
|
|
|
|
gnomAD: rs1800321,
|
|
|
|
|
|
ClinVar: RCV000011741, RCV000079082, RCV000268490, RCV001725114, RCV002311511
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with OTC deficiency (311250) caused by mutation in codon 45 (leu45-to-pro; 300461.0007), Grompe et al. (1989) identified a lys46-to-arg (K46R) polymorphism in the OTC gene (see also Hata et al., 1988). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
OTC, ARG245TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs72558454,
|
|
|
|
|
|
|
|
ClinVar: RCV000011746, RCV000083586
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family with OTC deficiency (311250), Finkelstein et al. (1990) identified a C-T change in the OTC gene, resulting in an arg245-to-trp (R245W) substitution. The patients showed some residual enzyme activity. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
OTC, IVS7DS, T-C, +2
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs72558431,
|
|
|
|
|
|
|
|
ClinVar: RCV000011743, RCV000083544
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with severe OTC deficiency (311250), Carstens et al. (1991) identified a C-T splice site mutation in the initial dinucleotide of intron 7 of the OTC gene, changing GT to GC and resulting in the skipping of exon 7 in the OTC cDNA. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
OTC, IVS7DS, A-G, +3
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs72558432,
|
|
|
|
|
|
|
|
ClinVar: RCV000011744, RCV000083545
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with severe OTC deficiency (311250), Carstens et al. (1991) identified a A-to-G splice site mutation in the third position of intron 7 of the OTC gene (GTA-GTG), resulting in skipping of exon 7 in the OTC cDNA. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
OTC, IVS4, A-T, -2
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs66556380,
|
|
|
|
|
|
|
|
ClinVar: RCV000011745, RCV000083419
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a case of severe OTC deficiency (311250), Carstens et al. (1991) found an A-T change in the 3-prime splice acceptor AG dinucleotide at the end of intron 4, making this region an unacceptable splice junction. As a result, a cryptic 3-prime splice acceptor within exon 5 was used, producing a deletion of the first 12 bp of exon 5 and the resulting mRNA. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
OTC, ARG277TRP
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000011746, RCV000083586
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated males with mild OTC deficiency (311250), Hata et al. (1991) identified a C-T change, resulting in an arg277-to-trp (R277W) substitution. In each family the affected male had an asymptomatic brother hemizygous for the mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
OTC, PRO225LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs67120076,
|
|
|
|
|
|
|
|
ClinVar: RCV000011747, RCV000083536
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Hentzen et al. (1991) described a family in which a proband and his maternal uncle and maternal great-uncle died in the neonatal period with hyperammonemia caused by OTC deficiency (311250). The mother and maternal grandmother of the proband showed a dramatic increment of urinary orotic acid following protein load, confirming their status as carriers. Using PCR amplification of OTC-specific mRNA derived from a postmortem biopsy of the liver of the proband, Hentzen et al. (1991) found that the MspI site (CCGG) in exon 7 was abolished. They identified a C-T transition in the OTC gene, resulting in a pro225-to-leu (P225L) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
OTC, GLU87LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs72554338,
|
|
|
|
|
|
|
|
ClinVar: RCV000011748, RCV000083376
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In order to improve the efficiency of screening for mutant OTC genotypes in cases of OTC deficiency (311250), Feldmann et al. (1992) focused on the carbamyl phosphate-binding domain (encoded by the third exon) and the MspI restriction sites (CCGG) of the coding sequence (located in exons 2 and 7), as they contain mutation hotspots, i.e., CpG dinucleotides. Using this strategy, Feldmann et al. (1992) identified 3 'new' mutant genotypes. One of the new mutations was a glu87-lys (E87K) mutation found in a male baby who did well for the first 3.5 months of life, but thereafter lost his appetite and failed to thrive. Vomiting, agitation, abnormal movements, and generalized seizures occurred at 7.5 months of age, and he rapidly fell into a deep terminal coma with liver enlargement and hepatic failure. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
OTC, GLY50TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs67486158,
|
|
|
|
|
|
gnomAD: rs67486158,
|
|
|
|
|
|
ClinVar: RCV000011749, RCV000083346
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Feldmann et al. (1992) found a gly50-to-ter (G50X) nonsense mutation in the OTC gene in a girl who was first admitted to hospital at the age of 8 months because of poor weight gain and vomiting. Hereditary fructose intolerance was first considered because of liver failure, but persistent hyperammonemia and increased urinary orotic acid led to the diagnosis of OTC deficiency (311250). Despite a low protein diet and arginine administration, the patient had repeated attacks of hyperammonemia. An orthotopic liver transplant was carried out at 5 years of age. Three years later the child was doing well on immunosuppressive agents. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
OTC, GLY162ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs66626662,
|
|
|
|
|
|
|
|
ClinVar: RCV000011750, RCV000083456
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male who died in deep coma at the age of 2 days, Feldmann et al. (1992) identified a glu162-to-arg (E162R) mutation, confirming OTC deficiency (311250). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
OTC, 1-BP DEL, 403G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs72556255,
|
|
|
|
|
|
gnomAD: rs72556255,
|
|
|
|
|
|
ClinVar: RCV000011751, RCV000083425
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male with neonatal onset of hyperammonemia due to OTC deficiency (311250), Tuchman et al. (1992) identified a 1-bp deletion in exon 5 of the OTC gene, a loss of guanine-403, causing a frameshift. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
OTC, IVS2, G-A, -1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs72554327,
|
|
|
|
|
|
|
|
ClinVar: RCV000011752, RCV000083365
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male with neonatal onset of hyperammonemia caused by OTC deficiency (311250), Tuchman et al. (1992) identified a G-A transition in the OTC gene at the 3-prime end of intron 2 involving nucleotide 217 (-1), resulting in an acceptor splicing site error. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
OTC, GLY47GLU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs72554331,
|
|
|
|
|
|
|
|
ClinVar: RCV000011753, RCV000083369
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male with neonatal onset of hyperammonemia caused by OTC deficiency (311250), Tuchman et al. (1992) identified a 236G-A transition in the OTC gene, resulting in a gly47-to-glu (G47E) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
OTC, ARG62THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs72554345,
|
|
|
|
|
|
|
|
ClinVar: RCV000011754, RCV000083388
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male in whom onset of clinical problems associated with OTC deficiency (311250) occurred after the neonatal period, Tuchman et al. (1992) identified a 281G-C transversion in exon 3 of the OTC gene, resulting in an arg62-to-thr (R62T) substitution. This substitution changed the composition of the putative active site for carbamyl phosphate. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
OTC, LEU272PHE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs72558465,
|
|
|
|
|
|
|
|
ClinVar: RCV000011755, RCV000083607
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male in whom onset of clinical problems associated with OTC deficiency (311250) occurred after the neonatal period, Tuchman et al. (1992) found a 912G-T transversion in exon 9 of the OTC gene, resulting in a leu272-to-phe (L272F) substitution. This changed a conserved domain of the gene, likely to be the ornithine binding site. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0024 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
OTC, TYR313ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs66469337,
|
|
|
|
|
|
|
|
ClinVar: RCV000011756, RCV000083325
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a female with OTC deficiency (311250), Tuchman et al. (1992) found a 1033T-G transversion in the OTC gene, resulting in a tyr313-to-asp (Y313D) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0025 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
OTC, ARG129HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs66656800,
|
|
|
|
|
|
|
|
ClinVar: RCV000011757, RCV000083414
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected patients from 2 Spanish families with OTC deficiency (311250), Garcia-Perez et al. (1995) identified an arg129-to-his (R129H) mutation in exon 4 of the OTC gene. The mutation results in the loss of a unique MspI restriction site that can be used for rapid diagnosis. The same mutation is found in the small spf-ash mouse, a rodent model of mild OTC deficiency, causing a neutral R129H mutation and inefficient splicing at the 5-prime donor site at the exon 4/intron 4 junction, with resultant 4 to 7% residual OTC activity. The mutation was found in the mother in one case, and arose de novo in the second case. Residual OTC activity, determined in a male and a female patient, was 1.3 and 3.5% of normal, respectively. Despite this low activity, the surviving patients had developed normally. One of them had reached reproductive age, raising the possibility of paternal transmission of the defect. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0026 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
OTC, LEU148PHE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs66741318,
|
|
|
|
|
|
|
|
ClinVar: RCV000011758, RCV000083441
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Komaki et al. (1997) identified a leu148-to-phe (L148F) substitution of the OTC gene in a 2-year-old girl with OTC deficiency (311250). OTC enzyme activity was 14% of control. Two elder sisters had died in childhood of hyperammonemia from OTC deficiency, and the patient also died of OTC deficiency. Enzyme activity in COS-1 cells transfected with the mutant cDNA was undetectable. Gene analysis showed that the mother had wildtype OTC alleles on both X chromosomes, and that the father was a mosaic for the mutant allele in his lymphocytes and spermatozoa. Thus, somatic and germline mosaicism led to the unusual pattern of X-linked inheritance in this family. Komaki et al. (1997) speculated about the possibility that skewed X inactivation, possibly due to inherited factors, was involved in this family. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0027 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
OTC, MET206ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs72558412,
|
|
|
|
|
|
|
|
ClinVar: RCV000011759, RCV000083513
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Bowling et al. (1999) reported a family with 2 consecutive males with OTC deficiency (311250), in which the mother had normal biochemical studies. OTC genotyping in both brothers showed a met206-to-arg (M206R) mutation in exon 6. Genotyping of the mother performed on peripheral blood leukocytes and skin fibroblasts showed no mutation, strongly suggesting gonadal mosaicism. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0028 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
OTC, ARG40CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs72554307,
|
|
|
|
|
|
gnomAD: rs72554307,
|
|
|
|
|
|
ClinVar: RCV000011760, RCV000083332
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Ploechl et al. (2001) reported on late-onset OTC deficiency (311250) in 2 families with mutations in the same codon, but with different base substitutions. Onset of symptoms showed great variation, and clinical diagnosis was late and difficult. In family A, with a C-T transition causing an arg40-to-cys (R40C) substitution in the OTC gene, hemizygous males died at ages 12 and 18 years. In family B, with a G-A transition causing an arg40-to-his (R40H) substitution (300461.0029), hemizygous males died at ages 20, 26, and 30 years. Whereas the R40C mutation is a private one, as in most cases of OTC deficiency, the R40H mutation is a recurrent one found first by Tuchman et al. (1994), and subsequently by Oppliger Leibundgut et al. (1995) and Matsuda et al. (1996). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0029 ORNITHINE TRANSCARBAMYLASE DEFICIENCY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
OTC, ARG40HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs72554308,
|
|
|
|
|
|
|
|
ClinVar: RCV000011761, RCV000083333
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>See 300461.0028 and Ploechl et al. (2001). </p><p>Mavinakere et al. (2001) used (35)S labeling to study import and processing of OTC carrying the R40H mutation in intact CHO cells and in isolated rat liver mitochondria compared to wildtype and OTC carrying an R141Q mutant that causes complete enzyme deficiency. OTC protein carrying the R40H mutation seemed to be imported and processed by the mitochondria in a manner similar to that of wildtype. However, it was consistently degraded to a smaller fragment in the intact cells, unlike the wildtype and R141Q mutant. The mature form of the enzyme was not susceptible to degradation. Mavinakere et al. (2001) concluded that deficiency in OTC enzymatic function conferred by the R40H mutation is likely caused by enhanced degradation of the preprotein in the cytosol. The authors further proposed that the variation in the rate of OTC turnover is responsible for the heterogeneity of the clinical phenotype in patients carrying this mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<span class="mim-text-font">
|
|
Finkelstein et al. (1989); Fox et al. (1986); Hoogenraad et al.
|
|
(1983)
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bonaiti-Pellie, C., Pelet, A., Ogier, H., Nelson, J.-R., Largilliere, C., Berthelot, J., Saudubray, J.-M., Munnich, A.
|
|
<strong>A probable sex difference in mutation rates in ornithine transcarbamylase deficiency.</strong>
|
|
Hum. Genet. 84: 163-166, 1990.
|
|
|
|
|
|
[PubMed: 2298452]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/BF00208933]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bowling, F., McGown, I., McGill, J., Cowley, D., Tuchman, M.
|
|
<strong>Maternal gonadal mosaicism causing ornithine transcarbamylase deficiency.</strong>
|
|
Am. J. Med. Genet. 85: 452-454, 1999.
|
|
|
|
|
|
[PubMed: 10405441]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/(sici)1096-8628(19990827)85:5<452::aid-ajmg4>3.0.co;2-4]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Carstens, R. P., Fenton, W. A., Rosenberg, L. R.
|
|
<strong>Identification of RNA splicing errors resulting in human ornithine transcarbamylase deficiency.</strong>
|
|
Am. J. Hum. Genet. 48: 1105-1114, 1991.
|
|
|
|
|
|
[PubMed: 2035531]
|
|
|
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Cotton, R. G. H., Rodrigues, N. R., Campbell, R. D.
|
|
<strong>Reactivity of cytosine and thymine in single-base-pair mismatches with hydroxylamine and osmium tetroxide and its application to the study of mutations.</strong>
|
|
Proc. Nat. Acad. Sci. 85: 4397-4401, 1988.
|
|
|
|
|
|
[PubMed: 3260032]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.85.12.4397]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
DeMars, R., LeVan, S. L., Trend, B. L., Russell, L. B.
|
|
<strong>Abnormal ornithine carbamyltransferase in mice having the sparse-fur mutation.</strong>
|
|
Proc. Nat. Acad. Sci. 73: 1693-1697, 1976.
|
|
|
|
|
|
[PubMed: 5727]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.73.5.1693]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Feldmann, D., Rozet, J.-M., Pelet, A., Hentzen, D., Briand, P., Hubert, P., Largilliere, C., Rabier, D., Farriaux, J.-P., Munnich, A.
|
|
<strong>Site specific screening for point mutations in ornithine transcarbamylase deficiency.</strong>
|
|
J. Med. Genet. 29: 471-475, 1992.
|
|
|
|
|
|
[PubMed: 1353535]
|
|
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Finkelstein, J. E., Francomano, C. A., Brusilow, S. W., Traystman, M. D.
|
|
<strong>Use of denaturing gradient gel electrophoresis for detection of mutation and prospective diagnosis in late onset ornithine transcarbamylase deficiency.</strong>
|
|
Genomics 7: 167-172, 1990.
|
|
|
|
|
|
[PubMed: 2347583]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/0888-7543(90)90537-5]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Finkelstein, J. E., Hauser, E., Brusilow, S. W.
|
|
<strong>Late onset ornithine transcarbamylase deficiency (OTCD) in males. (Abstract)</strong>
|
|
Am. J. Hum. Genet. 45 (suppl.): A5, 1989.
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Fox, J. E., Hack, A. M., Fenton, W. A., Rosenberg, L. E.
|
|
<strong>Identification and application of additional restriction fragment length polymorphisms at the human ornithine transcarbamylase locus.</strong>
|
|
Am. J. Hum. Genet. 38: 841-847, 1986.
|
|
|
|
|
|
[PubMed: 3014867]
|
|
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Garcia-Perez, M. A., Sanjurjo, P., Rubio, V.
|
|
<strong>Demonstration of the spf-ash mutation in Spanish patients with ornithine transcarbamylase deficiency of moderate severity.</strong>
|
|
Hum. Genet. 95: 183-186, 1995.
|
|
|
|
|
|
[PubMed: 7860064]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/BF00209398]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Genet, S., Cranston, T., Middleton-Price, H. R.
|
|
<strong>Mutation detection in 65 families with a possible diagnosis of ornithine carbamoyltransferase deficiency including 14 novel mutations.</strong>
|
|
J. Inherit. Metab. Dis. 23: 669-676, 2000.
|
|
|
|
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