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Entry
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- *605197 - KYNURENINASE; KYNU
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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">*605197</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li 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="#biochemicalFeatures">Biochemical Features</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<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/605197">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000115919;t=ENST00000264170" 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=8942" 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=605197" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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<div 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=ENSG00000115919;t=ENST00000264170" 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_001032998,NM_001199241,NM_003937,XM_017005217,XM_047446250,XM_047446251,XM_047446252,XM_047446253" 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_003937" 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=605197" 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 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=08940&isoform_id=08940_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/KYNU" 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/1323715,3913982,4504937,12654129,48146963,62702233,62822178,62898413,74101437,119632004,119632005,119632006,158255236,158257622,189067483,312839880,1034617490,2217331888,2217331891,2217331893,2217331895,2462578249,2462578251,2462578253,2462578255" 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/Q16719" 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=8942" 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=ENSG00000115919;t=ENST00000264170" 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=KYNU" 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=KYNU" 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+8942" 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/KYNU" 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:8942" 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/8942" 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=chr2&hgg_gene=ENST00000264170.9&hgg_start=142877664&hgg_end=143055833&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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:6469" 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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=605197[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=605197[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000115919" 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=KYNU" 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=KYNU" 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=KYNU" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=KYNU&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/PA30258" 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:6469" 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:1918039" 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/KYNU#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:1918039" 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/8942/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=8942" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00015802;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-120215-204" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:8942" 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=KYNU&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> 17820009, 33116002, 72945002<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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605197
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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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KYNURENINASE; KYNU
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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L-KYNURENINE HYDROLASE
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=KYNU" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">KYNU</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/2/670?start=-3&limit=10&highlight=670">2q22.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr2:142877664-143055833&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'})">2:142,877,664-143,055,833</a> </span>
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</em>
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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<span class="hidden-sm hidden-xs pull-right">
|
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<a href="/clinicalSynopsis/table?mimNumber=236800,617661" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
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</a>
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</span>
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="2">
|
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<span class="mim-font">
|
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<a href="/geneMap/2/670?start=-3&limit=10&highlight=670">
|
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2q22.2
|
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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?Hydroxykynureninuria
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<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
|
|
<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
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</span>
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/236800"> 236800 </a>
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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<tr>
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<td>
|
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<span class="mim-font">
|
|
Vertebral, cardiac, renal, and limb defects syndrome 2
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
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|
<a href="/entry/617661"> 617661 </a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
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|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
|
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/605197" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<p>Kynureninase (<a href="https://enzyme.expasy.org/EC/3.7.1.33" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 3.7.1.33</a>) is a 3-hydroxykynureninase-type enzyme involved in the kynurenine pathway for the biosynthesis of NAD cofactors from tryptophan. It catalyzes the conversion of L-3-hydroxykynurenine and L-kynurenine to 3-hydroxyanthranilic acid and anthranilic acid, respectively. The reaction is pyridoxal-5-prime-dependent and is sensitive to nutritional vitamin B6 deprivation in mammals. Studies in mouse, rat, and pig suggest that kynureninase is a 95-kD kD homodimer predominantly located in the cytoplasm (<a href="#8" class="mim-tip-reference" title="Toma, S., Nakamura, M., Tone, S., Okuno, E., Kido, R., Breton, J., Avanzi, N., Cozzi, L., Speciale, C., Mostardini, M., Gatti, S., Benatti, L. <strong>Cloning and recombinant expression of rat and human kynureninase.</strong> FEBS Lett. 408: 5-10, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9180257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9180257</a>] [<a href="https://doi.org/10.1016/s0014-5793(97)00374-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9180257">Toma et al., 1997</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9180257" 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>Kynureninase is also involved in the de novo NAD(H) synthesis pathway, using niacin from dietary input (summary by <a href="#6" class="mim-tip-reference" title="Shi, H., Enriquez, A., Rapadas, M., Martin, E. M. M. A., Wang, R., Moreau, J., Lim, C. K., Szot, J. O., Ip, E., Hughes, J. N., Sugimoto, K., Humphreys, D. T., and 21 others. <strong>NAD deficiency, congenital malformations, and niacin supplementation.</strong> New Eng. J. Med. 377: 544-552, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28792876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28792876</a>] [<a href="https://doi.org/10.1056/NEJMoa1616361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28792876">Shi et al., 2017</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28792876" 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="#1" class="mim-tip-reference" title="Alberati-Giani, D., Buchli, R., Malherbe, P., Broger, C., Lang, G., Kohler, C., Lahm, H.-W., Cesura, A. M. <strong>Isolation and expression of a cDNA clone encoding human kynureninase.</strong> Europ. J. Biochem. 239: 460-468, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8706755/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8706755</a>] [<a href="https://doi.org/10.1111/j.1432-1033.1996.0460u.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8706755">Alberati-Giani et al. (1996)</a> purified rat liver kynureninase and obtained amino acid sequence from tryptic peptides. Using a partial rat kidney cDNA cloned by degenerate RT-PCR to screen a human hepatoma cell cDNA library, they isolated a KYNU cDNA encoding a deduced 465-amino acid protein. Using the same approach, <a href="#8" class="mim-tip-reference" title="Toma, S., Nakamura, M., Tone, S., Okuno, E., Kido, R., Breton, J., Avanzi, N., Cozzi, L., Speciale, C., Mostardini, M., Gatti, S., Benatti, L. <strong>Cloning and recombinant expression of rat and human kynureninase.</strong> FEBS Lett. 408: 5-10, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9180257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9180257</a>] [<a href="https://doi.org/10.1016/s0014-5793(97)00374-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9180257">Toma et al. (1997)</a> also isolated a human kynureninase cDNA clone. Human KYNU shares 48% and 85% amino acid identity with a putative yeast kynureninase and rat kynureninase, respectively. Both research groups identified a conserved lysine residue (lys276) thought to be the critical residue for cofactor binding within the pyridoxal-P-binding site consensus sequence. By Northern blot analysis, <a href="#1" class="mim-tip-reference" title="Alberati-Giani, D., Buchli, R., Malherbe, P., Broger, C., Lang, G., Kohler, C., Lahm, H.-W., Cesura, A. M. <strong>Isolation and expression of a cDNA clone encoding human kynureninase.</strong> Europ. J. Biochem. 239: 460-468, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8706755/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8706755</a>] [<a href="https://doi.org/10.1111/j.1432-1033.1996.0460u.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8706755">Alberati-Giani et al. (1996)</a> detected strong expression of a 2-kb transcript in liver, placenta, and lung, with weaker expression in heart, brain, skeletal muscle, kidney, and pancreas. They also detected strong expression of a 2.6-kb transcript in placenta and liver, with weaker expression in heart, skeletal muscle, and pancreas. Using a recombinant kynureninase cDNA expressed in cell lines, <a href="#1" class="mim-tip-reference" title="Alberati-Giani, D., Buchli, R., Malherbe, P., Broger, C., Lang, G., Kohler, C., Lahm, H.-W., Cesura, A. M. <strong>Isolation and expression of a cDNA clone encoding human kynureninase.</strong> Europ. J. Biochem. 239: 460-468, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8706755/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8706755</a>] [<a href="https://doi.org/10.1111/j.1432-1033.1996.0460u.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8706755">Alberati-Giani et al. (1996)</a> and <a href="#8" class="mim-tip-reference" title="Toma, S., Nakamura, M., Tone, S., Okuno, E., Kido, R., Breton, J., Avanzi, N., Cozzi, L., Speciale, C., Mostardini, M., Gatti, S., Benatti, L. <strong>Cloning and recombinant expression of rat and human kynureninase.</strong> FEBS Lett. 408: 5-10, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9180257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9180257</a>] [<a href="https://doi.org/10.1016/s0014-5793(97)00374-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9180257">Toma et al. (1997)</a> observed kynureninase and hydroxykynureninase activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9180257+8706755" 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>Elevated levels of kynureninase activity have been observed in cerebral and systemic inflammatory conditions (<a href="#4" class="mim-tip-reference" title="Heyes, M. P., Saito, K., Major, E. O., Milstein, S., Markey, S. P., Vickers, J. H. <strong>A mechanism of quinolinic acid formation by brain in inflammatory neurological disease: attenuation of synthesis from L-tryptophan by 6-chlorotryptophan and 4-chloro-3-hydroxyanthranilate.</strong> Brain 116: 1425-1450, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8293279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8293279</a>] [<a href="https://doi.org/10.1093/brain/116.6.1425" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8293279">Heyes et al., 1993</a>). A deficiency of kynureninase has been associated with abnormal tryptophan metabolism; see hydroxykynureninuria (<a href="/entry/236800">236800</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8293279" 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="#3" class="mim-tip-reference" title="Gross, M. B. <strong>Personal Communication.</strong> Baltimore, Md. 5/30/2014."None>Gross (2014)</a> mapped the KYNU gene to chromosome 2q22.2 based on an alignment of the KYNU sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=BC000879" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">BC000879</a>) with the genomic sequence (GRCh37).</p>
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<a href="#2" class="mim-tip-reference" title="Christensen, M., Duno, M., Lund, A. M., Skovby, F., Christensen, E. <strong>Xanthurenic aciduria due to a mutation in KYNU encoding kynureninase.</strong> J. Inherit. Metab. Dis. 30: 248-255, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17334708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17334708</a>] [<a href="https://doi.org/10.1007/s10545-007-0396-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17334708">Christensen et al. (2007)</a> reported 2 brothers with a homozygous missense mutation (T198A; <a href="#0001">605197.0001</a>) in the KYNU gene. Both boys had high excretions of xanthurenic acid, kynurenin, and 3-hydroxykynurenin in urine (hydroxykynureninuria; <a href="/entry/236800">236800</a>), but were otherwise well. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17334708" 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>Vertebral, Cardiac, Renal, and Limb Defects Syndrome 2</em></strong></p><p>
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In 2 unrelated children with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; <a href="/entry/617661">617661</a>), <a href="#6" class="mim-tip-reference" title="Shi, H., Enriquez, A., Rapadas, M., Martin, E. M. M. A., Wang, R., Moreau, J., Lim, C. K., Szot, J. O., Ip, E., Hughes, J. N., Sugimoto, K., Humphreys, D. T., and 21 others. <strong>NAD deficiency, congenital malformations, and niacin supplementation.</strong> New Eng. J. Med. 377: 544-552, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28792876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28792876</a>] [<a href="https://doi.org/10.1056/NEJMoa1616361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28792876">Shi et al. (2017)</a> identified homozygous or compound heterozygous truncating mutations in the KYNU gene (<a href="#0003">605197.0003</a>-<a href="#0005">605197.0005</a>). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. In vitro functional expression studies showed that the mutations essentially abolished KYNU enzymatic activity. Analysis of plasma from 1 patient (patient D) showed increased levels of the upstream metabolite 3HK and decreased levels of the downstream metabolites NAD and NAH(H). Studies in mice, which have different niacin levels compared to humans, indicated that the congenital malformations found in humans resulted from deficient NAD levels rather than increased 3HK levels. <a href="#6" class="mim-tip-reference" title="Shi, H., Enriquez, A., Rapadas, M., Martin, E. M. M. A., Wang, R., Moreau, J., Lim, C. K., Szot, J. O., Ip, E., Hughes, J. N., Sugimoto, K., Humphreys, D. T., and 21 others. <strong>NAD deficiency, congenital malformations, and niacin supplementation.</strong> New Eng. J. Med. 377: 544-552, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28792876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28792876</a>] [<a href="https://doi.org/10.1056/NEJMoa1616361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28792876">Shi et al. (2017)</a> noted that NAD is a cofactor with broad cellular effects, including ATP production, macromolecular biosynthesis, redox reactions, energy metabolism, DNA repair, and modulation of transcription factors, all of which play an important role in embryogenesis. <a href="#6" class="mim-tip-reference" title="Shi, H., Enriquez, A., Rapadas, M., Martin, E. M. M. A., Wang, R., Moreau, J., Lim, C. K., Szot, J. O., Ip, E., Hughes, J. N., Sugimoto, K., Humphreys, D. T., and 21 others. <strong>NAD deficiency, congenital malformations, and niacin supplementation.</strong> New Eng. J. Med. 377: 544-552, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28792876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28792876</a>] [<a href="https://doi.org/10.1056/NEJMoa1616361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28792876">Shi et al. (2017)</a> theorized that niacin supplementation could be of benefit in such patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28792876" 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 5-year-old girl with VCRL2 who was clinically diagnosed with Catel-Manzke syndrome (see <a href="/entry/616145">616145</a>), <a href="#5" class="mim-tip-reference" title="Schule, I., Berger, U., Matysiak, U., Ruzaike, G., Stiller, B., Poul, M., Spiekerkoetter, U., Lausch, E., Grunert, S. C., Schmidts, M. <strong>A homozygous deletion of exon 5 of KYNU resulting from a maternal chromosome 2 isodisomy (UPD2) causes Catel-Manzke-syndrome/VCRL syndrome.</strong> Genes (Basel) 12: 879, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34200361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34200361</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34200361[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/10.3390/genes12060879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34200361">Schule et al. (2021)</a> identified homozygosity for deletion of exon 5 of the KYNU gene. Exon 5 contains 62 bp (c.374_436del, NM_00119924.1) and the deletion is predicted to result in a frameshift and premature termination (p.125_145delLeu146TyrfsTer). The deletion breakpoints (chr2:142,954,376 and chr2:142,955,239, GRCh38), encompassing 835 bp (<a href="#0006">605197.0006</a>), were confirmed by CGH array and long-range PCR. SNP array showed that the homozygous mutation arose from maternal uniparental isodisomy of chromosome 2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34200361" 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 4 unrelated patients with VCRL2, <a href="#7" class="mim-tip-reference" title="Szot, J. O., Slavotinek, A., Chong, K., Brandau, O., Nezarati, M., Cueto-Gonzalez, A. M., Patel, M. S., Devine, W. P., Rego, S., Acyinena, A. P., Shannon, P., Myles-Reid, D., and 17 others. <strong>New cases that expand the genotypic and phenotypic spectrum of congenital NAD deficiency disorder.</strong> Hum. Mutat. 42: 862-876, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33942433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33942433</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33942433[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.24211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33942433">Szot et al. (2021)</a> identified compound heterozygous or homozygous mutations in the KYNU gene (see, e.g., <a href="#0007">605197.0007</a>-<a href="#0010">605197.0010</a>). Yeast with a homozygous knockout for bna5, the yeast ortholog of human KYNU, were transformed with plasmids containing KYNU with each of the mutations or with wildtype KYNU. Transfection with each of 4 mutant KYNU plasmids resulted in smaller yeast mass compared to wildtype when grown in niacin-free culture media. NAD levels were reduced in the yeast transformed with any of the 6 mutant KYNU plasmids compared to wildtype. <a href="#7" class="mim-tip-reference" title="Szot, J. O., Slavotinek, A., Chong, K., Brandau, O., Nezarati, M., Cueto-Gonzalez, A. M., Patel, M. S., Devine, W. P., Rego, S., Acyinena, A. P., Shannon, P., Myles-Reid, D., and 17 others. <strong>New cases that expand the genotypic and phenotypic spectrum of congenital NAD deficiency disorder.</strong> Hum. Mutat. 42: 862-876, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33942433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33942433</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33942433[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.24211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33942433">Szot et al. (2021)</a> concluded that the compromised growth and/or NAD content of the bna5 knockout yeast transfected with each mutant KYNU was a result of impaired KYNU function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33942433" 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="#6" class="mim-tip-reference" title="Shi, H., Enriquez, A., Rapadas, M., Martin, E. M. M. A., Wang, R., Moreau, J., Lim, C. K., Szot, J. O., Ip, E., Hughes, J. N., Sugimoto, K., Humphreys, D. T., and 21 others. <strong>NAD deficiency, congenital malformations, and niacin supplementation.</strong> New Eng. J. Med. 377: 544-552, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28792876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28792876</a>] [<a href="https://doi.org/10.1056/NEJMoa1616361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28792876">Shi et al. (2017)</a> found that Kynu-null mice were viable and normal. Plasma analysis showed increased 3HK levels, but normal NAD levels. The authors noted that mice have increased niacin levels compared to humans and that mouse embryos may receive niacin from their mothers, resulting in a buffering effect on genetic-based NAD deficiency. These findings suggested that the congenital malformations found in humans resulted from deficient NAD levels. Indeed, further studies in mutant mice born to mothers on a niacin-free diet showed that NAD deficiency due to lack of Kynu resulted in multiple defects, including defects in vertebral segmentation, heart defects, small kidney, cleft palate, talipes, syndactyly, and caudal agenesis. Supplementation of Kynu-null mouse embryos with niacin during gestation restored NAD levels and prevented the disruption of embryogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28792876" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a Somali boy, born to consanguineous parents, who was noted on urine metabolic screening to have high excretions of xanthurenic acid, kynurenin, and 3-hydroxykynurenin, characteristic of hydroxykynureninuria (<a href="/entry/236800">236800</a>), <a href="#2" class="mim-tip-reference" title="Christensen, M., Duno, M., Lund, A. M., Skovby, F., Christensen, E. <strong>Xanthurenic aciduria due to a mutation in KYNU encoding kynureninase.</strong> J. Inherit. Metab. Dis. 30: 248-255, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17334708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17334708</a>] [<a href="https://doi.org/10.1007/s10545-007-0396-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17334708">Christensen et al. (2007)</a> identified homozygosity for a c.593A-T transversion in the KYNU gene, resulting in a thr198-to-ala (T198A) substitution. The patient presented with jaundice and vomiting at 9 days of age. He recovered in a matter of days and was well, with normal milestones and free from medication, at follow-up at age 6 years. This mutation was also found in homozygosity in the patient's brother, who also had high excretions of tryptophan metabolites. Both parents and 1 sib were heterozygous for the mutation; 2 remaining sibs did not carry the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17334708" 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> rs2304705 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2304705;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/rs2304705?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=rs2304705" 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=rs2304705" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>This variant is classified as a variant of unknown significance because its contribution to essential hypertension (see <a href="/entry/145500">145500</a>) has not been confirmed.</p><p><a href="#9" class="mim-tip-reference" title="Zhang, Y., Shen, J., He, X., Zhang, K., Wu, S., Xiao, B., Zhou, X., Phillips, R. S., Gao, P., Jeunemaitre, X., Zhu, D. <strong>A rare variant at the KYNU gene is associated with kynureninase activity and essential hypertension in the Han Chinese population.</strong> Circ. Cardiovasc. Genet. 4: 687-694, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22012986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22012986</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.110.959064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22012986">Zhang et al. (2011)</a> studied a rare variant of KYNU that resulted in an arg188-to-gln substitution (R188Q), in relation to kynureninase activity and essential hypertension. A linkage peak for essential hypertension had been detected in the Han Chinese population (<a href="#10" class="mim-tip-reference" title="Zhu, D. L., Wang, H. Y., Xiong, M. M., He, X., Chu, S. L., Jin, L., Wang, G. L., Yuan, W. T., Zhao, G. S., Boerwinkle, E., Huang, W. <strong>Linkage of hypertension to chromosome 2q14-q23 in Chinese families.</strong> J. Hypertens. 19: 55-61, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11204305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11204305</a>] [<a href="https://doi.org/10.1097/00004872-200101000-00008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11204305">Zhu et al., 2001</a>). <a href="#9" class="mim-tip-reference" title="Zhang, Y., Shen, J., He, X., Zhang, K., Wu, S., Xiao, B., Zhou, X., Phillips, R. S., Gao, P., Jeunemaitre, X., Zhu, D. <strong>A rare variant at the KYNU gene is associated with kynureninase activity and essential hypertension in the Han Chinese population.</strong> Circ. Cardiovasc. Genet. 4: 687-694, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22012986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22012986</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.110.959064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22012986">Zhang et al. (2011)</a> found that 33 of 1,124 Chinese patients with hypertension were heterozygous for R188Q, whereas only 14 of 1,084 normotensive controls were heterozygous for this mutation (188Q allele frequency, 0.015 vs 0.006; p = 0.0075). A genotype-discordant sib-pair study was performed in another 924 individuals from 213 families, indicating that 188Q carriers had higher systolic blood pressure (168.29 +/- 24.67 vs 139.00 +/- 12.82 mm Hg, p less than 0.001) and diastolic blood pressure (105.50 +/- 14.08 vs 90.75 +/- 11.07 mm Hg, p = 0.001) than did R188 homozygous sibs. The R188Q variant was found to be rarer in 2 other ethnic groups (3 heterozygous among 880 hypertensive French whites and 0 of 90 black Africans with hypertension). <a href="#9" class="mim-tip-reference" title="Zhang, Y., Shen, J., He, X., Zhang, K., Wu, S., Xiao, B., Zhou, X., Phillips, R. S., Gao, P., Jeunemaitre, X., Zhu, D. <strong>A rare variant at the KYNU gene is associated with kynureninase activity and essential hypertension in the Han Chinese population.</strong> Circ. Cardiovasc. Genet. 4: 687-694, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22012986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22012986</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.110.959064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22012986">Zhang et al. (2011)</a> found that the kynureninase activity in plasma was correlated with blood pressure in subjects from hypertensive families (p less than 0.05). The kinetic Michaelis constant of 188Q carriers was lower than that of R188 homozygous subjects (0.05 +/- 0.02 vs 0.10 +/- 0.02 mmol/L, p = 0.005). R188Q mutation in vitro also showed less catalytic efficiency than the wildtype KYNU enzyme (maximal reaction velocity/kinetic Michaelis constant ratio, 0.050 +/- 0.012 vs 0.11 +/- 0.016 mL/min per mg; p = 0.029). <a href="#9" class="mim-tip-reference" title="Zhang, Y., Shen, J., He, X., Zhang, K., Wu, S., Xiao, B., Zhou, X., Phillips, R. S., Gao, P., Jeunemaitre, X., Zhu, D. <strong>A rare variant at the KYNU gene is associated with kynureninase activity and essential hypertension in the Han Chinese population.</strong> Circ. Cardiovasc. Genet. 4: 687-694, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22012986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22012986</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.110.959064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22012986">Zhang et al. (2011)</a> concluded that the rare KYNU variant R188Q affects kynureninase activity, and that their results are consistent with the hypothesis that this mutation can predispose to essential hypertension. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22012986+11204305" 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> rs1135401744 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1135401744;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/rs1135401744?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=rs1135401744" 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=rs1135401744" 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=RCV000496147 OR RCV000505804" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000496147, RCV000505804" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000496147...</a>
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<p>In a female infant (<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=SCV000540921" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ClinVar\', \'domain\': \'ncbi.nlm.nih.gov\'})">SCV000540921</a>), born of consanguineous Lebanese parents (family C), with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; <a href="/entry/617661">617661</a>), <a href="#6" class="mim-tip-reference" title="Shi, H., Enriquez, A., Rapadas, M., Martin, E. M. M. A., Wang, R., Moreau, J., Lim, C. K., Szot, J. O., Ip, E., Hughes, J. N., Sugimoto, K., Humphreys, D. T., and 21 others. <strong>NAD deficiency, congenital malformations, and niacin supplementation.</strong> New Eng. J. Med. 377: 544-552, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28792876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28792876</a>] [<a href="https://doi.org/10.1056/NEJMoa1616361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28792876">Shi et al. (2017)</a> identified a homozygous G-to-T transversion (c.170-1G-T) in intron 2 of the KYNU gene, resulting in a splice site alteration and premature termination (Val57GlufsTer21). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the ExAC database and was classified as pathogenic based on the American College of Medical Genetics guidelines. In vitro functional expression studies showed that the mutation essentially abolished KYNU enzymatic activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28792876" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 VERTEBRAL, CARDIAC, RENAL, AND LIMB DEFECTS SYNDROME 2</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> rs758865880 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs758865880;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/rs758865880?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=rs758865880" 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=rs758865880" 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=RCV000496184 OR RCV000505808 OR RCV000522905" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000496184, RCV000505808, RCV000522905" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000496184...</a>
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<p>In a 3-year-old girl (<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=SCV000540922" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ClinVar\', \'domain\': \'ncbi.nlm.nih.gov\'})">SCV000540922</a>), born of unrelated parents of North American origin (family D), with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; <a href="/entry/617661">617661</a>), <a href="#6" class="mim-tip-reference" title="Shi, H., Enriquez, A., Rapadas, M., Martin, E. M. M. A., Wang, R., Moreau, J., Lim, C. K., Szot, J. O., Ip, E., Hughes, J. N., Sugimoto, K., Humphreys, D. T., and 21 others. <strong>NAD deficiency, congenital malformations, and niacin supplementation.</strong> New Eng. J. Med. 377: 544-552, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28792876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28792876</a>] [<a href="https://doi.org/10.1056/NEJMoa1616361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28792876">Shi et al. (2017)</a> identified compound heterozygous truncating mutations in the KYNU gene: a c.468T-A transversion in exon 6, resulting in a tyr156-to-ter (Y156X) substitution, and a 7-bp deletion (c.1045_1051delTTTAAGC; <a href="#0005">605197.0005</a>) in exon 13, resulting in a frameshift and premature termination (Phe349LysfsTer4). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variants were filtered against the ExAC database and were classified as pathogenic based on the American College of Medical Genetics guidelines. In vitro functional expression studies showed that the mutations essentially abolished KYNU enzymatic activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28792876" 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> rs770642379 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs770642379;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/rs770642379?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=rs770642379" 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=rs770642379" 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=RCV000496114 OR RCV000505812 OR RCV000520521" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000496114, RCV000505812, RCV000520521" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000496114...</a>
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<p>For discussion of the 7-bp deletion (c.1045_1051del) in the KYNU gene, resulting in a frameshift and premature termination (Phe349LysfsTer4), that was found in compound heterozygous state in a patient (<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=SCV000540923" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ClinVar\', \'domain\': \'ncbi.nlm.nih.gov\'})">SCV000540923</a>) with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; <a href="/entry/617661">617661</a>) by <a href="#6" class="mim-tip-reference" title="Shi, H., Enriquez, A., Rapadas, M., Martin, E. M. M. A., Wang, R., Moreau, J., Lim, C. K., Szot, J. O., Ip, E., Hughes, J. N., Sugimoto, K., Humphreys, D. T., and 21 others. <strong>NAD deficiency, congenital malformations, and niacin supplementation.</strong> New Eng. J. Med. 377: 544-552, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28792876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28792876</a>] [<a href="https://doi.org/10.1056/NEJMoa1616361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28792876">Shi et al. (2017)</a>, see <a href="#0004">605197.0004</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28792876" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 VERTEBRAL, CARDIAC, RENAL, AND LIMB DEFECTS SYNDROME 2</strong>
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KYNU, 835-BP DEL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV002265065" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002265065" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002265065</a>
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<p>In a 5-year-old girl with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; <a href="/entry/617661">617661</a>) who was clinically diagnosed with Catel-Manzke syndrome (see <a href="/entry/616145">616145</a>), <a href="#5" class="mim-tip-reference" title="Schule, I., Berger, U., Matysiak, U., Ruzaike, G., Stiller, B., Poul, M., Spiekerkoetter, U., Lausch, E., Grunert, S. C., Schmidts, M. <strong>A homozygous deletion of exon 5 of KYNU resulting from a maternal chromosome 2 isodisomy (UPD2) causes Catel-Manzke-syndrome/VCRL syndrome.</strong> Genes (Basel) 12: 879, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34200361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34200361</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34200361[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/10.3390/genes12060879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34200361">Schule et al. (2021)</a> identified homozygosity for deletion of exon 5 (EX5DEL) of the KYNU gene. Exon 5 contains 62 bp (c.374_436del, NM_00119924.1) and the deletion is predicted to result in a frameshift and premature termination (p.125_145delLeu146TyrfsTer). The deletion breakpoints (chr2:142,954,376 and chr2:142,955,239, GRCh38), encompassing 835 bp, were confirmed by CGH array and long-range PCR. SNP array showed that the homozygous mutation arose from maternal uniparental isodisomy of chromosome 2. The patient had increased excretion of xanthurenic acid in her urine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34200361" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 VERTEBRAL, CARDIAC, RENAL, AND LIMB DEFECTS SYNDROME 2</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">rs1458654786 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1458654786;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=rs1458654786" 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=rs1458654786" 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=RCV001391062 OR RCV003883466" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001391062, RCV003883466" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001391062...</a>
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<p>In a stillborn infant, born of consanguineous Sri Lankan parents (family 4), with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; <a href="/entry/617661">617661</a>), <a href="#7" class="mim-tip-reference" title="Szot, J. O., Slavotinek, A., Chong, K., Brandau, O., Nezarati, M., Cueto-Gonzalez, A. M., Patel, M. S., Devine, W. P., Rego, S., Acyinena, A. P., Shannon, P., Myles-Reid, D., and 17 others. <strong>New cases that expand the genotypic and phenotypic spectrum of congenital NAD deficiency disorder.</strong> Hum. Mutat. 42: 862-876, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33942433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33942433</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33942433[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.24211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33942433">Szot et al. (2021)</a> identified a homozygous c.788A-G transition (c.788A-G, NM_003937.3) in the KYNU gene, resulting in a his263-to-arg (H263R) substitution. The mutation was identified by trio whole-exome sequencing and the parents were shown to be mutation carriers. The mutation was not present in the gnomAD database. Yeast with a homozygous knockout for bna5, the yeast ortholog of KYNU, were transformed with plasmids containing KYNU with the H263R mutation or with wildtype KYNU. The mutant KYNU resulted in smaller yeast mass compared to wildtype when grown in niacin-free culture media. The NAD level was also reduced in the yeast transformed with the mutant KYNU plasmid compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33942433" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 VERTEBRAL, CARDIAC, RENAL, AND LIMB DEFECTS SYNDROME 2</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> rs765122670 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs765122670;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/rs765122670?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=rs765122670" 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=rs765122670" 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=RCV001391063 OR RCV003883467" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001391063, RCV003883467" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001391063...</a>
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<p>In a patient, born of unrelated Sri Lankan parents (family 5), with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; <a href="/entry/617661">617661</a>), <a href="#7" class="mim-tip-reference" title="Szot, J. O., Slavotinek, A., Chong, K., Brandau, O., Nezarati, M., Cueto-Gonzalez, A. M., Patel, M. S., Devine, W. P., Rego, S., Acyinena, A. P., Shannon, P., Myles-Reid, D., and 17 others. <strong>New cases that expand the genotypic and phenotypic spectrum of congenital NAD deficiency disorder.</strong> Hum. Mutat. 42: 862-876, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33942433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33942433</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33942433[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.24211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33942433">Szot et al. (2021)</a> identified a homozygous c.616G-A transition (c.616G-A, NM_003937.3) in the KYNU gene resulting in a glu206-to-lys (E206K) substitution. The mutation was identified by trio whole-exome sequencing and the parents were shown to be mutation carriers. The mutation was present in the gnomAD database at an allele frequency of 0.0000199. Yeast with a homozygous knockout for bna5, the yeast ortholog of KYNU, were transformed with plasmids containing KYNU with the E206K mutation or with wildtype KYNU. The yeast transformed with the mutant KYNU plasmid had a reduced NAD level compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33942433" 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>.0009 VERTEBRAL, CARDIAC, RENAL, AND LIMB DEFECTS SYNDROME 2</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> rs767060858 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs767060858;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/rs767060858?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=rs767060858" 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=rs767060858" 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=RCV001391064 OR RCV003883468" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001391064, RCV003883468" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001391064...</a>
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<p>In a Caucasian patient (family 6) with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; 617661), <a href="#7" class="mim-tip-reference" title="Szot, J. O., Slavotinek, A., Chong, K., Brandau, O., Nezarati, M., Cueto-Gonzalez, A. M., Patel, M. S., Devine, W. P., Rego, S., Acyinena, A. P., Shannon, P., Myles-Reid, D., and 17 others. <strong>New cases that expand the genotypic and phenotypic spectrum of congenital NAD deficiency disorder.</strong> Hum. Mutat. 42: 862-876, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33942433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33942433</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33942433[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.24211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33942433">Szot et al. (2021)</a> identified compound heterozygous mutations in the KYNU gene: a 3-bp deletion (c.361_363del, NM_003937.3), resulting in deletion of lys121 (Lys121del), and a c.1035T-A transversion, resulting in a ser345-to-arg (S345R; <a href="#0010">605197.0010</a>) substitution. The mutation was identified by whole-exome sequencing and the parents were shown to be mutation carriers. The c.361_363del mutation was present in the gnomAD database at an allele frequency of 0.0000177 and the S345R mutation was not present in gnomAD. Yeast with a homozygous knockout for bna5, the yeast ortholog of KYNU, were transformed with plasmids containing KYNU with the c.361_363del or S345R mutation or with wildtype KYNU. Yeast transformed with S345R mutant KYNU resulted in smaller yeast mass compared to wildtype when grown in niacin-free culture media. Yeast transformed with the c.361_363del or S345R mutant KYNU plasmids had reduced NAD levels compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33942433" 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>.0010 VERTEBRAL, CARDIAC, RENAL, AND LIMB DEFECTS SYNDROME 2</strong>
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KYNU, SER345ARG
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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> rs771131526 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs771131526;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/rs771131526?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=rs771131526" 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=rs771131526" 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=RCV001391065 OR RCV003883469" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001391065, RCV003883469" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001391065...</a>
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<span class="mim-text-font">
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<p>For discussion of the c.1035T-A transversion (c.1035T-A, NM_003937.3) in the KYNU gene, resulting in a ser345-to-arg (S345R) substitution, that was found in compound heterozygous state in a patient with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; <a href="/entry/617661">617661</a>) by <a href="#7" class="mim-tip-reference" title="Szot, J. O., Slavotinek, A., Chong, K., Brandau, O., Nezarati, M., Cueto-Gonzalez, A. M., Patel, M. S., Devine, W. P., Rego, S., Acyinena, A. P., Shannon, P., Myles-Reid, D., and 17 others. <strong>New cases that expand the genotypic and phenotypic spectrum of congenital NAD deficiency disorder.</strong> Hum. Mutat. 42: 862-876, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33942433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33942433</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33942433[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.24211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33942433">Szot et al. (2021)</a>, see <a href="#0009">605197.0009</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33942433" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
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<a id="Alberati-Giani1996" class="mim-anchor"></a>
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Alberati-Giani, D., Buchli, R., Malherbe, P., Broger, C., Lang, G., Kohler, C., Lahm, H.-W., Cesura, A. M.
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<strong>Isolation and expression of a cDNA clone encoding human kynureninase.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8706755/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8706755</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8706755" 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/10.1111/j.1432-1033.1996.0460u.x" target="_blank">Full Text</a>]
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<a id="Christensen2007" class="mim-anchor"></a>
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Christensen, M., Duno, M., Lund, A. M., Skovby, F., Christensen, E.
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<strong>Xanthurenic aciduria due to a mutation in KYNU encoding kynureninase.</strong>
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J. Inherit. Metab. Dis. 30: 248-255, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17334708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17334708</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17334708" 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/s10545-007-0396-2" target="_blank">Full Text</a>]
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<a id="Gross2014" class="mim-anchor"></a>
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Gross, M. B.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 5/30/2014.
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<a id="Heyes1993" class="mim-anchor"></a>
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Heyes, M. P., Saito, K., Major, E. O., Milstein, S., Markey, S. P., Vickers, J. H.
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<strong>A mechanism of quinolinic acid formation by brain in inflammatory neurological disease: attenuation of synthesis from L-tryptophan by 6-chlorotryptophan and 4-chloro-3-hydroxyanthranilate.</strong>
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Brain 116: 1425-1450, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8293279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8293279</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8293279" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/116.6.1425" target="_blank">Full Text</a>]
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Schule, I., Berger, U., Matysiak, U., Ruzaike, G., Stiller, B., Poul, M., Spiekerkoetter, U., Lausch, E., Grunert, S. C., Schmidts, M.
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<strong>A homozygous deletion of exon 5 of KYNU resulting from a maternal chromosome 2 isodisomy (UPD2) causes Catel-Manzke-syndrome/VCRL syndrome.</strong>
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Genes (Basel) 12: 879, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34200361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34200361</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34200361[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34200361" 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/10.3390/genes12060879" target="_blank">Full Text</a>]
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Shi, H., Enriquez, A., Rapadas, M., Martin, E. M. M. A., Wang, R., Moreau, J., Lim, C. K., Szot, J. O., Ip, E., Hughes, J. N., Sugimoto, K., Humphreys, D. T., and 21 others.
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<strong>NAD deficiency, congenital malformations, and niacin supplementation.</strong>
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New Eng. J. Med. 377: 544-552, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28792876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28792876</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28792876" 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/10.1056/NEJMoa1616361" target="_blank">Full Text</a>]
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<a id="7" class="mim-anchor"></a>
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<a id="Szot2021" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Szot, J. O., Slavotinek, A., Chong, K., Brandau, O., Nezarati, M., Cueto-Gonzalez, A. M., Patel, M. S., Devine, W. P., Rego, S., Acyinena, A. P., Shannon, P., Myles-Reid, D., and 17 others.
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<strong>New cases that expand the genotypic and phenotypic spectrum of congenital NAD deficiency disorder.</strong>
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Hum. Mutat. 42: 862-876, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33942433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33942433</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33942433[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33942433" 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.24211" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="8" class="mim-anchor"></a>
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<a id="Toma1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Toma, S., Nakamura, M., Tone, S., Okuno, E., Kido, R., Breton, J., Avanzi, N., Cozzi, L., Speciale, C., Mostardini, M., Gatti, S., Benatti, L.
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<strong>Cloning and recombinant expression of rat and human kynureninase.</strong>
|
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FEBS Lett. 408: 5-10, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9180257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9180257</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9180257" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0014-5793(97)00374-8" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="9" class="mim-anchor"></a>
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<a id="Zhang2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, Y., Shen, J., He, X., Zhang, K., Wu, S., Xiao, B., Zhou, X., Phillips, R. S., Gao, P., Jeunemaitre, X., Zhu, D.
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<strong>A rare variant at the KYNU gene is associated with kynureninase activity and essential hypertension in the Han Chinese population.</strong>
|
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Circ. Cardiovasc. Genet. 4: 687-694, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22012986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22012986</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22012986" 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/10.1161/CIRCGENETICS.110.959064" target="_blank">Full Text</a>]
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</p>
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</li>
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<li>
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<a id="10" class="mim-anchor"></a>
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<a id="Zhu2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhu, D. L., Wang, H. Y., Xiong, M. M., He, X., Chu, S. L., Jin, L., Wang, G. L., Yuan, W. T., Zhao, G. S., Boerwinkle, E., Huang, W.
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<strong>Linkage of hypertension to chromosome 2q14-q23 in Chinese families.</strong>
|
|
J. Hypertens. 19: 55-61, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11204305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11204305</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11204305" 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/10.1097/00004872-200101000-00008" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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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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<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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</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 : 07/11/2022
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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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Cassandra L. Kniffin - updated : 09/20/2017<br>Ada Hamosh - updated : 11/21/2014<br>Matthew B. Gross - updated : 5/30/2014
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="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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Dawn Watkins-Chow : 8/3/2000
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="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 : 03/06/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 03/04/2024<br>carol : 03/01/2024<br>carol : 02/29/2024<br>carol : 07/11/2022<br>joanna : 10/30/2017<br>carol : 09/21/2017<br>ckniffin : 09/20/2017<br>carol : 05/24/2017<br>alopez : 05/23/2017<br>alopez : 11/24/2014<br>alopez : 11/21/2014<br>joanna : 7/14/2014<br>mgross : 5/30/2014<br>alopez : 2/25/2014<br>carol : 8/8/2000
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</span>
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</div>
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</div>
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</div>
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</div>
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</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> 605197
|
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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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KYNURENINASE; KYNU
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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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L-KYNURENINE HYDROLASE
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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: KYNU</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> 17820009, 33116002, 72945002;
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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: 2q22.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 2:142,877,664-143,055,833 </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>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
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<tr class="active">
|
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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|
Phenotype <br /> MIM number
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</th>
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<th>
|
|
Inheritance
|
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</th>
|
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<th>
|
|
Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
|
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<tbody>
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|
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<tr>
|
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<td rowspan="2">
|
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<span class="mim-font">
|
|
2q22.2
|
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</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
?Hydroxykynureninuria
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
236800
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
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</span>
|
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
|
|
Vertebral, cardiac, renal, and limb defects syndrome 2
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
617661
|
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
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</h4>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
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<strong>Description</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Kynureninase (EC 3.7.1.33) is a 3-hydroxykynureninase-type enzyme involved in the kynurenine pathway for the biosynthesis of NAD cofactors from tryptophan. It catalyzes the conversion of L-3-hydroxykynurenine and L-kynurenine to 3-hydroxyanthranilic acid and anthranilic acid, respectively. The reaction is pyridoxal-5-prime-dependent and is sensitive to nutritional vitamin B6 deprivation in mammals. Studies in mouse, rat, and pig suggest that kynureninase is a 95-kD kD homodimer predominantly located in the cytoplasm (Toma et al., 1997). </p><p>Kynureninase is also involved in the de novo NAD(H) synthesis pathway, using niacin from dietary input (summary by Shi et al., 2017). </p>
|
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</span>
|
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<div>
|
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<br />
|
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
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</h4>
|
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</div>
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|
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<span class="mim-text-font">
|
|
<p>Alberati-Giani et al. (1996) purified rat liver kynureninase and obtained amino acid sequence from tryptic peptides. Using a partial rat kidney cDNA cloned by degenerate RT-PCR to screen a human hepatoma cell cDNA library, they isolated a KYNU cDNA encoding a deduced 465-amino acid protein. Using the same approach, Toma et al. (1997) also isolated a human kynureninase cDNA clone. Human KYNU shares 48% and 85% amino acid identity with a putative yeast kynureninase and rat kynureninase, respectively. Both research groups identified a conserved lysine residue (lys276) thought to be the critical residue for cofactor binding within the pyridoxal-P-binding site consensus sequence. By Northern blot analysis, Alberati-Giani et al. (1996) detected strong expression of a 2-kb transcript in liver, placenta, and lung, with weaker expression in heart, brain, skeletal muscle, kidney, and pancreas. They also detected strong expression of a 2.6-kb transcript in placenta and liver, with weaker expression in heart, skeletal muscle, and pancreas. Using a recombinant kynureninase cDNA expressed in cell lines, Alberati-Giani et al. (1996) and Toma et al. (1997) observed kynureninase and hydroxykynureninase activity. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Biochemical Features</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
<span class="mim-text-font">
|
|
<p>Elevated levels of kynureninase activity have been observed in cerebral and systemic inflammatory conditions (Heyes et al., 1993). A deficiency of kynureninase has been associated with abnormal tryptophan metabolism; see hydroxykynureninuria (236800). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Gross (2014) mapped the KYNU gene to chromosome 2q22.2 based on an alignment of the KYNU sequence (GenBank BC000879) with the genomic sequence (GRCh37).</p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
|
<span class="mim-text-font">
|
|
<p><strong><em>Hydroxykynureninuria</em></strong></p><p>
|
|
Christensen et al. (2007) reported 2 brothers with a homozygous missense mutation (T198A; 605197.0001) in the KYNU gene. Both boys had high excretions of xanthurenic acid, kynurenin, and 3-hydroxykynurenin in urine (hydroxykynureninuria; 236800), but were otherwise well. </p><p><strong><em>Vertebral, Cardiac, Renal, and Limb Defects Syndrome 2</em></strong></p><p>
|
|
In 2 unrelated children with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; 617661), Shi et al. (2017) identified homozygous or compound heterozygous truncating mutations in the KYNU gene (605197.0003-605197.0005). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. In vitro functional expression studies showed that the mutations essentially abolished KYNU enzymatic activity. Analysis of plasma from 1 patient (patient D) showed increased levels of the upstream metabolite 3HK and decreased levels of the downstream metabolites NAD and NAH(H). Studies in mice, which have different niacin levels compared to humans, indicated that the congenital malformations found in humans resulted from deficient NAD levels rather than increased 3HK levels. Shi et al. (2017) noted that NAD is a cofactor with broad cellular effects, including ATP production, macromolecular biosynthesis, redox reactions, energy metabolism, DNA repair, and modulation of transcription factors, all of which play an important role in embryogenesis. Shi et al. (2017) theorized that niacin supplementation could be of benefit in such patients. </p><p>In a 5-year-old girl with VCRL2 who was clinically diagnosed with Catel-Manzke syndrome (see 616145), Schule et al. (2021) identified homozygosity for deletion of exon 5 of the KYNU gene. Exon 5 contains 62 bp (c.374_436del, NM_00119924.1) and the deletion is predicted to result in a frameshift and premature termination (p.125_145delLeu146TyrfsTer). The deletion breakpoints (chr2:142,954,376 and chr2:142,955,239, GRCh38), encompassing 835 bp (605197.0006), were confirmed by CGH array and long-range PCR. SNP array showed that the homozygous mutation arose from maternal uniparental isodisomy of chromosome 2. </p><p>In 4 unrelated patients with VCRL2, Szot et al. (2021) identified compound heterozygous or homozygous mutations in the KYNU gene (see, e.g., 605197.0007-605197.0010). Yeast with a homozygous knockout for bna5, the yeast ortholog of human KYNU, were transformed with plasmids containing KYNU with each of the mutations or with wildtype KYNU. Transfection with each of 4 mutant KYNU plasmids resulted in smaller yeast mass compared to wildtype when grown in niacin-free culture media. NAD levels were reduced in the yeast transformed with any of the 6 mutant KYNU plasmids compared to wildtype. Szot et al. (2021) concluded that the compromised growth and/or NAD content of the bna5 knockout yeast transfected with each mutant KYNU was a result of impaired KYNU function. </p>
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</span>
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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>Shi et al. (2017) found that Kynu-null mice were viable and normal. Plasma analysis showed increased 3HK levels, but normal NAD levels. The authors noted that mice have increased niacin levels compared to humans and that mouse embryos may receive niacin from their mothers, resulting in a buffering effect on genetic-based NAD deficiency. These findings suggested that the congenital malformations found in humans resulted from deficient NAD levels. Indeed, further studies in mutant mice born to mothers on a niacin-free diet showed that NAD deficiency due to lack of Kynu resulted in multiple defects, including defects in vertebral segmentation, heart defects, small kidney, cleft palate, talipes, syndactyly, and caudal agenesis. Supplementation of Kynu-null mouse embryos with niacin during gestation restored NAD levels and prevented the disruption of embryogenesis. </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>10 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 HYDROXYKYNURENINURIA (1 family)</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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KYNU, THR198ALA
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<br />
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SNP: rs606231307,
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gnomAD: rs606231307,
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ClinVar: RCV000148021
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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 Somali boy, born to consanguineous parents, who was noted on urine metabolic screening to have high excretions of xanthurenic acid, kynurenin, and 3-hydroxykynurenin, characteristic of hydroxykynureninuria (236800), Christensen et al. (2007) identified homozygosity for a c.593A-T transversion in the KYNU gene, resulting in a thr198-to-ala (T198A) substitution. The patient presented with jaundice and vomiting at 9 days of age. He recovered in a matter of days and was well, with normal milestones and free from medication, at follow-up at age 6 years. This mutation was also found in homozygosity in the patient's brother, who also had high excretions of tryptophan metabolites. Both parents and 1 sib were heterozygous for the mutation; 2 remaining sibs did not carry the mutation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 VARIANT OF UNKNOWN SIGNIFICANCE</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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KYNU, ARG188GLN
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<br />
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SNP: rs2304705,
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gnomAD: rs2304705,
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ClinVar: RCV000148022, RCV003387772
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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>This variant is classified as a variant of unknown significance because its contribution to essential hypertension (see 145500) has not been confirmed.</p><p>Zhang et al. (2011) studied a rare variant of KYNU that resulted in an arg188-to-gln substitution (R188Q), in relation to kynureninase activity and essential hypertension. A linkage peak for essential hypertension had been detected in the Han Chinese population (Zhu et al., 2001). Zhang et al. (2011) found that 33 of 1,124 Chinese patients with hypertension were heterozygous for R188Q, whereas only 14 of 1,084 normotensive controls were heterozygous for this mutation (188Q allele frequency, 0.015 vs 0.006; p = 0.0075). A genotype-discordant sib-pair study was performed in another 924 individuals from 213 families, indicating that 188Q carriers had higher systolic blood pressure (168.29 +/- 24.67 vs 139.00 +/- 12.82 mm Hg, p less than 0.001) and diastolic blood pressure (105.50 +/- 14.08 vs 90.75 +/- 11.07 mm Hg, p = 0.001) than did R188 homozygous sibs. The R188Q variant was found to be rarer in 2 other ethnic groups (3 heterozygous among 880 hypertensive French whites and 0 of 90 black Africans with hypertension). Zhang et al. (2011) found that the kynureninase activity in plasma was correlated with blood pressure in subjects from hypertensive families (p less than 0.05). The kinetic Michaelis constant of 188Q carriers was lower than that of R188 homozygous subjects (0.05 +/- 0.02 vs 0.10 +/- 0.02 mmol/L, p = 0.005). R188Q mutation in vitro also showed less catalytic efficiency than the wildtype KYNU enzyme (maximal reaction velocity/kinetic Michaelis constant ratio, 0.050 +/- 0.012 vs 0.11 +/- 0.016 mL/min per mg; p = 0.029). Zhang et al. (2011) concluded that the rare KYNU variant R188Q affects kynureninase activity, and that their results are consistent with the hypothesis that this mutation can predispose to essential hypertension. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 VERTEBRAL, CARDIAC, RENAL, AND LIMB DEFECTS SYNDROME 2</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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KYNU, IVS2AS, G-T, -1
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<br />
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SNP: rs1135401744,
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gnomAD: rs1135401744,
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ClinVar: RCV000496147, RCV000505804
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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 infant (SCV000540921), born of consanguineous Lebanese parents (family C), with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; 617661), Shi et al. (2017) identified a homozygous G-to-T transversion (c.170-1G-T) in intron 2 of the KYNU gene, resulting in a splice site alteration and premature termination (Val57GlufsTer21). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the ExAC database and was classified as pathogenic based on the American College of Medical Genetics guidelines. In vitro functional expression studies showed that the mutation essentially abolished KYNU enzymatic activity. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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|
<span class="mim-font">
|
|
<strong>.0004 VERTEBRAL, CARDIAC, RENAL, AND LIMB DEFECTS SYNDROME 2</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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KYNU, TYR156TER
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<br />
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SNP: rs758865880,
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gnomAD: rs758865880,
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ClinVar: RCV000496184, RCV000505808, RCV000522905
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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 3-year-old girl (SCV000540922), born of unrelated parents of North American origin (family D), with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; 617661), Shi et al. (2017) identified compound heterozygous truncating mutations in the KYNU gene: a c.468T-A transversion in exon 6, resulting in a tyr156-to-ter (Y156X) substitution, and a 7-bp deletion (c.1045_1051delTTTAAGC; 605197.0005) in exon 13, resulting in a frameshift and premature termination (Phe349LysfsTer4). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variants were filtered against the ExAC database and were classified as pathogenic based on the American College of Medical Genetics guidelines. In vitro functional expression studies showed that the mutations essentially abolished KYNU enzymatic activity. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 VERTEBRAL, CARDIAC, RENAL, AND LIMB DEFECTS SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
|
KYNU, 7-BP DEL, NT1045
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|
<br />
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|
|
SNP: rs770642379,
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|
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gnomAD: rs770642379,
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|
|
ClinVar: RCV000496114, RCV000505812, RCV000520521
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 7-bp deletion (c.1045_1051del) in the KYNU gene, resulting in a frameshift and premature termination (Phe349LysfsTer4), that was found in compound heterozygous state in a patient (SCV000540923) with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; 617661) by Shi et al. (2017), see 605197.0004. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 VERTEBRAL, CARDIAC, RENAL, AND LIMB DEFECTS SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
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|
|
KYNU, 835-BP DEL
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|
<br />
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|
|
ClinVar: RCV002265065
|
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|
|
</span>
|
|
</div>
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 5-year-old girl with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; 617661) who was clinically diagnosed with Catel-Manzke syndrome (see 616145), Schule et al. (2021) identified homozygosity for deletion of exon 5 (EX5DEL) of the KYNU gene. Exon 5 contains 62 bp (c.374_436del, NM_00119924.1) and the deletion is predicted to result in a frameshift and premature termination (p.125_145delLeu146TyrfsTer). The deletion breakpoints (chr2:142,954,376 and chr2:142,955,239, GRCh38), encompassing 835 bp, were confirmed by CGH array and long-range PCR. SNP array showed that the homozygous mutation arose from maternal uniparental isodisomy of chromosome 2. The patient had increased excretion of xanthurenic acid in her urine. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 VERTEBRAL, CARDIAC, RENAL, AND LIMB DEFECTS SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
KYNU, HIS263ARG
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<br />
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|
|
SNP: rs1458654786,
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|
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ClinVar: RCV001391062, RCV003883466
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|
|
</span>
|
|
</div>
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a stillborn infant, born of consanguineous Sri Lankan parents (family 4), with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; 617661), Szot et al. (2021) identified a homozygous c.788A-G transition (c.788A-G, NM_003937.3) in the KYNU gene, resulting in a his263-to-arg (H263R) substitution. The mutation was identified by trio whole-exome sequencing and the parents were shown to be mutation carriers. The mutation was not present in the gnomAD database. Yeast with a homozygous knockout for bna5, the yeast ortholog of KYNU, were transformed with plasmids containing KYNU with the H263R mutation or with wildtype KYNU. The mutant KYNU resulted in smaller yeast mass compared to wildtype when grown in niacin-free culture media. The NAD level was also reduced in the yeast transformed with the mutant KYNU plasmid compared to wildtype. </p>
|
|
</span>
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</div>
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 VERTEBRAL, CARDIAC, RENAL, AND LIMB DEFECTS SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
KYNU, GLU206LYS
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|
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|
|
|
<br />
|
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|
|
SNP: rs765122670,
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|
|
|
gnomAD: rs765122670,
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|
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ClinVar: RCV001391063, RCV003883467
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|
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|
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient, born of unrelated Sri Lankan parents (family 5), with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; 617661), Szot et al. (2021) identified a homozygous c.616G-A transition (c.616G-A, NM_003937.3) in the KYNU gene resulting in a glu206-to-lys (E206K) substitution. The mutation was identified by trio whole-exome sequencing and the parents were shown to be mutation carriers. The mutation was present in the gnomAD database at an allele frequency of 0.0000199. Yeast with a homozygous knockout for bna5, the yeast ortholog of KYNU, were transformed with plasmids containing KYNU with the E206K mutation or with wildtype KYNU. The yeast transformed with the mutant KYNU plasmid had a reduced NAD level compared to wildtype. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 VERTEBRAL, CARDIAC, RENAL, AND LIMB DEFECTS SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
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<span class="mim-text-font">
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KYNU, 3-BP DEL, NT361
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|
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|
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<br />
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|
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SNP: rs767060858,
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|
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gnomAD: rs767060858,
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ClinVar: RCV001391064, RCV003883468
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Caucasian patient (family 6) with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; 617661), Szot et al. (2021) identified compound heterozygous mutations in the KYNU gene: a 3-bp deletion (c.361_363del, NM_003937.3), resulting in deletion of lys121 (Lys121del), and a c.1035T-A transversion, resulting in a ser345-to-arg (S345R; 605197.0010) substitution. The mutation was identified by whole-exome sequencing and the parents were shown to be mutation carriers. The c.361_363del mutation was present in the gnomAD database at an allele frequency of 0.0000177 and the S345R mutation was not present in gnomAD. Yeast with a homozygous knockout for bna5, the yeast ortholog of KYNU, were transformed with plasmids containing KYNU with the c.361_363del or S345R mutation or with wildtype KYNU. Yeast transformed with S345R mutant KYNU resulted in smaller yeast mass compared to wildtype when grown in niacin-free culture media. Yeast transformed with the c.361_363del or S345R mutant KYNU plasmids had reduced NAD levels compared to wildtype. </p>
|
|
</span>
|
|
</div>
|
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|
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<div>
|
|
<br />
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</div>
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</div>
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<div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 VERTEBRAL, CARDIAC, RENAL, AND LIMB DEFECTS SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
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KYNU, SER345ARG
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<br />
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SNP: rs771131526,
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|
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gnomAD: rs771131526,
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ClinVar: RCV001391065, RCV003883469
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
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<p>For discussion of the c.1035T-A transversion (c.1035T-A, NM_003937.3) in the KYNU gene, resulting in a ser345-to-arg (S345R) substitution, that was found in compound heterozygous state in a patient with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; 617661) by Szot et al. (2021), see 605197.0009. </p>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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Alberati-Giani, D., Buchli, R., Malherbe, P., Broger, C., Lang, G., Kohler, C., Lahm, H.-W., Cesura, A. M.
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<strong>Isolation and expression of a cDNA clone encoding human kynureninase.</strong>
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Europ. J. Biochem. 239: 460-468, 1996.
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[PubMed: 8706755]
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[Full Text: https://doi.org/10.1111/j.1432-1033.1996.0460u.x]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Christensen, M., Duno, M., Lund, A. M., Skovby, F., Christensen, E.
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<strong>Xanthurenic aciduria due to a mutation in KYNU encoding kynureninase.</strong>
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J. Inherit. Metab. Dis. 30: 248-255, 2007.
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[PubMed: 17334708]
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[Full Text: https://doi.org/10.1007/s10545-007-0396-2]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Gross, M. B.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 5/30/2014.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Heyes, M. P., Saito, K., Major, E. O., Milstein, S., Markey, S. P., Vickers, J. H.
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<strong>A mechanism of quinolinic acid formation by brain in inflammatory neurological disease: attenuation of synthesis from L-tryptophan by 6-chlorotryptophan and 4-chloro-3-hydroxyanthranilate.</strong>
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Brain 116: 1425-1450, 1993.
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[PubMed: 8293279]
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[Full Text: https://doi.org/10.1093/brain/116.6.1425]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Schule, I., Berger, U., Matysiak, U., Ruzaike, G., Stiller, B., Poul, M., Spiekerkoetter, U., Lausch, E., Grunert, S. C., Schmidts, M.
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<strong>A homozygous deletion of exon 5 of KYNU resulting from a maternal chromosome 2 isodisomy (UPD2) causes Catel-Manzke-syndrome/VCRL syndrome.</strong>
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Genes (Basel) 12: 879, 2021.
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[PubMed: 34200361]
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[Full Text: https://doi.org/10.3390/genes12060879]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Shi, H., Enriquez, A., Rapadas, M., Martin, E. M. M. A., Wang, R., Moreau, J., Lim, C. K., Szot, J. O., Ip, E., Hughes, J. N., Sugimoto, K., Humphreys, D. T., and 21 others.
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<strong>NAD deficiency, congenital malformations, and niacin supplementation.</strong>
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New Eng. J. Med. 377: 544-552, 2017.
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[PubMed: 28792876]
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[Full Text: https://doi.org/10.1056/NEJMoa1616361]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Szot, J. O., Slavotinek, A., Chong, K., Brandau, O., Nezarati, M., Cueto-Gonzalez, A. M., Patel, M. S., Devine, W. P., Rego, S., Acyinena, A. P., Shannon, P., Myles-Reid, D., and 17 others.
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<strong>New cases that expand the genotypic and phenotypic spectrum of congenital NAD deficiency disorder.</strong>
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Hum. Mutat. 42: 862-876, 2021.
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[PubMed: 33942433]
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[Full Text: https://doi.org/10.1002/humu.24211]
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<li>
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Toma, S., Nakamura, M., Tone, S., Okuno, E., Kido, R., Breton, J., Avanzi, N., Cozzi, L., Speciale, C., Mostardini, M., Gatti, S., Benatti, L.
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<strong>Cloning and recombinant expression of rat and human kynureninase.</strong>
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FEBS Lett. 408: 5-10, 1997.
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[PubMed: 9180257]
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[Full Text: https://doi.org/10.1016/s0014-5793(97)00374-8]
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Zhang, Y., Shen, J., He, X., Zhang, K., Wu, S., Xiao, B., Zhou, X., Phillips, R. S., Gao, P., Jeunemaitre, X., Zhu, D.
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<strong>A rare variant at the KYNU gene is associated with kynureninase activity and essential hypertension in the Han Chinese population.</strong>
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Circ. Cardiovasc. Genet. 4: 687-694, 2011.
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[PubMed: 22012986]
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[Full Text: https://doi.org/10.1161/CIRCGENETICS.110.959064]
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Zhu, D. L., Wang, H. Y., Xiong, M. M., He, X., Chu, S. L., Jin, L., Wang, G. L., Yuan, W. T., Zhao, G. S., Boerwinkle, E., Huang, W.
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<strong>Linkage of hypertension to chromosome 2q14-q23 in Chinese families.</strong>
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J. Hypertens. 19: 55-61, 2001.
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[PubMed: 11204305]
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[Full Text: https://doi.org/10.1097/00004872-200101000-00008]
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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 : 07/11/2022<br>Cassandra L. Kniffin - updated : 09/20/2017<br>Ada Hamosh - updated : 11/21/2014<br>Matthew B. Gross - updated : 5/30/2014
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Dawn Watkins-Chow : 8/3/2000
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