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Entry
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- *131222 - THYMIDINE PHOSPHORYLASE; TYMP
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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">*131222</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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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="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/131222">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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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=ENSG00000025708;t=ENST00000252029" 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=1890" 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=131222" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000025708;t=ENST00000252029" 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_001113755,NM_001113756,NM_001257988,NM_001257989,NM_001953" 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_001953" 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=131222" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=08833&isoform_id=08833_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/TYMP" 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/189701,4503445,6862560,17390355,30354553,67477361,119593966,119593967,119593968,119593969,119593970,166158922,166158925,189054487,193787063,194375323,194384890,311348698,311348700,311348702,311348704,311348706,311348708,311348710,311348712,311348714,311348716,311348718,311348720,311348722,311348724,311348726,311348728,311348730,311348732,311348734,311348736,311348738,311348740,311348742,311348744,311348746,311348748,311348750,311348752,311348754,311348756,311348758,311348760,311348762,311348764,311348766,311348768,311348770,311348772,311348774,311348776,384229049,384229051,957949306,957949310,957949313" 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/P19971" 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=1890" 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=ENSG00000025708;t=ENST00000252029" 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=TYMP" 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=TYMP" 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+1890" 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/TYMP" 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:1890" 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/1890" 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=chr22&hgg_gene=ENST00000252029.8&hgg_start=50525752&hgg_end=50530085&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:3148" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:3148" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/tymp" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=131222[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=131222[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/ENSG00000025708" 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=TYMP" 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=TYMP" 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=TYMP" 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=TYMP&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/PA162407502" 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:3148" 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:1920212" 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/TYMP#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:1920212" 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/1890/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=1890" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-100415-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
|
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</div>
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</a>
|
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:1890" 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=TYMP&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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</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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131222
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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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THYMIDINE PHOSPHORYLASE; TYMP
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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">
|
|
TP<br />
|
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ENDOTHELIAL CELL GROWTH FACTOR, PLATELET-DERIVED; ECGF; ECGF1<br />
|
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PLATELET-DERIVED ENDOTHELIAL CELL GROWTH FACTOR; PDECGF<br />
|
|
GLIOSTATIN
|
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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=TYMP" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TYMP</a></em></strong>
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/22/417?start=-3&limit=10&highlight=417">22q13.33</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr22:50525752-50530085&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'})">22:50,525,752-50,530,085</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</div>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
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<th>
|
|
Phenotype
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</th>
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<th>
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|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
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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="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/22/417?start=-3&limit=10&highlight=417">
|
|
22q13.33
|
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</a>
|
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</span>
|
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</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Mitochondrial DNA depletion syndrome 1 (MNGIE type)
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/603041"> 603041 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
|
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/131222" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/131222" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
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<p>The TYMP gene encodes thymidine phosphorylase (<a href="https://enzyme.expasy.org/EC/2.4.2.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 2.4.2.4</a>), a cytosolic enzyme that catalyzes the phosphorylation of thymidine or deoxyuridine to thymine or uracil, and is thus essential for the nucleotide salvage pathway (review by <a href="#15" class="mim-tip-reference" title="Suomalainen, A., Isohanni, P. <strong>Mitochondrial DNA depletion syndromes: many genes, common mechanisms.</strong> Neuromusc. Disord. 20: 429-437, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20444604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20444604</a>] [<a href="https://doi.org/10.1016/j.nmd.2010.03.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20444604">Suomalainen and Isohanni, 2010</a>). The protein product was originally identified as platelet-derived endothelial cell growth factor (PDECGF), an angiogenic factor distinct from the previously described endothelial cell mitogens of the fibroblast growth factor family (<a href="#7" class="mim-tip-reference" title="Ishikawa, F., Miyazono, K., Hellman, U., Drexler, H., Wernstedt, C., Hagiwara, K., Usuki, K., Takaku, F., Risau, W., Heldin, C.-H. <strong>Identification of angiogenic activity and the cloning and expression of platelet-derived endothelial cell growth factor.</strong> Nature 338: 557-562, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2467210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2467210</a>] [<a href="https://doi.org/10.1038/338557a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2467210">Ishikawa et al., 1989</a>). PDECGF is stored in platelets as a 45-kD single polypeptide chain and has a highly restricted target cell specificity acting only on endothelial cells. It promotes angiogenesis in vivo, and stimulates the in vitro growth of a variety of endothelial cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20444604+2467210" 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="#7" class="mim-tip-reference" title="Ishikawa, F., Miyazono, K., Hellman, U., Drexler, H., Wernstedt, C., Hagiwara, K., Usuki, K., Takaku, F., Risau, W., Heldin, C.-H. <strong>Identification of angiogenic activity and the cloning and expression of platelet-derived endothelial cell growth factor.</strong> Nature 338: 557-562, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2467210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2467210</a>] [<a href="https://doi.org/10.1038/338557a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2467210">Ishikawa et al. (1989)</a> isolated clones corresponding to the PDECGF gene from a placenta cDNA library. The deduced 482-residue protein had a molecular mass of 49.97 kD; Northern blot analysis detected a 1.8-kb mRNA transcript. Expression studies showed that the clone had growth-promoting activity for porcine aortic endothelial cells and a chemotactic effect for bovine endothelial cells, as well as angiogenic activity in mouse tumors. The findings confirmed that PDECGF acts as a potent angiogenic factor and likely plays a role in the maintenance of blood vessels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2467210" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Usuki, K., Saras, J., Waltenberger, J., Miyazono, K., Pierce, G., Thomason, A., Heldin, C.-H. <strong>Platelet-derived endothelial cell growth factor has thymidine phosphorylase activity.</strong> Biochem. Biophys. Res. Commun. 184: 1311-1316, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1590793/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1590793</a>] [<a href="https://doi.org/10.1016/s0006-291x(05)80025-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1590793">Usuki et al. (1992)</a> found that the PDECGF protein shared 39.2% amino acid sequence similarity over a 439-amino acid region with thymidine phosphorylase in E. coli. They found that the enzyme occurs as a 90-kD homodimer, similar to other thymidine phosphorylases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1590793" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Asai, K., Nakanishi, K., Isobe, I., Eksioglu, Y. Z., Hirano, A., Hama, K., Miyamoto, T., Kato, T. <strong>Neurotrophic action of gliostatin on cortical neurons: identity of gliostatin and platelet-derived endothelial cell growth factor.</strong> J. Biol. Chem. 267: 20311-20316, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1400349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1400349</a>]" pmid="1400349">Asai et al. (1992)</a> found that gliostatin, a homodimeric structure of two 50-kD subunits, was identical to PDECGF. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1400349" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Matsukawa, K., Moriyama, A., Kawai, Y., Asai, K., Kato, T. <strong>Tissue distribution of human gliostatin/platelet-derived endothelial cell growth factor (PD-ECGF) and its drug-induced expression.</strong> Biochim. Biophys. Acta 1314: 71-82, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8972720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8972720</a>] [<a href="https://doi.org/10.1016/s0167-4889(96)00078-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8972720">Matsukawa et al. (1996)</a> found ubiquitous expression of the PDECGF gene in various human tissues and organs, with relatively high levels in the digestive system, including esophagus and rectum, as well as in brain, spleen, bladder and lung. There was little or no expression in gallbladder, aorta, muscle, fat, and kidney. In addition, most human tumor cell lines showed 4- or 5-fold higher expression of the protein than normal tissue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8972720" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#4" class="mim-tip-reference" title="Hagiwara, K., Stenman, G., Honda, H., Sahlin, P., Andersson, A., Miyazono, K., Heldin, C. H., Ishikawa, F., Takaku, F. <strong>Organization and chromosomal localization of the human platelet-derived endothelial cell growth factor gene.</strong> Molec. Cell. Biol. 11: 2125-2132, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2005900/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2005900</a>] [<a href="https://doi.org/10.1128/mcb.11.4.2125-2132.1991" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2005900">Hagiwara et al. (1991)</a> determined that the PDECGF gene contains 10 exons spanning more than 4.3 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2005900" 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>Using an ECGF1 cDNA probe, Stenman et al. (<a href="#14" class="mim-tip-reference" title="Stenman, G., Sahlin, P., Hagiwara, K., Dumanski, J., Collins, V., Heldin, C.-H. <strong>Mapping of the human platelet-derived endothelial cell growth factor (PD-ECGF) gene to chromosome 22q13. (Abstract)</strong> Cytogenet. Cell Genet. 58: 2051 only, 1991."None>1991</a>, <a href="#13" class="mim-tip-reference" title="Stenman, G., Sahlin, P., Dumanski, J. P., Hagiwara, K., Ishikawa, F., Miyazono, K., Collins, V. P., Heldin, C.-H. <strong>Regional localization of the human platelet-derived endothelial cell growth factor (ECGF1) gene to chromosome 22q13.</strong> Cytogenet. Cell Genet. 59: 22-23, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1733667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1733667</a>] [<a href="https://doi.org/10.1159/000133191" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1733667">1992</a>) assigned the ECGF1 gene to chromosome 22 by analysis of its segregation in a panel of human/rodent somatic cell hybrids. By in situ hybridization, they sublocalized the gene to 22q13. The ECGF1 gene is in the same region as the PDGFB gene (<a href="/entry/190040">190040</a>) but is located distal to the 22q13 breakpoint in hybrid 1/22AM27, while PDGFB is proximal to this breakpoint. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1733667" 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="#17" class="mim-tip-reference" title="Usuki, K., Saras, J., Waltenberger, J., Miyazono, K., Pierce, G., Thomason, A., Heldin, C.-H. <strong>Platelet-derived endothelial cell growth factor has thymidine phosphorylase activity.</strong> Biochem. Biophys. Res. Commun. 184: 1311-1316, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1590793/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1590793</a>] [<a href="https://doi.org/10.1016/s0006-291x(05)80025-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1590793">Usuki et al. (1992)</a> demonstrated that PDECGF has thymidine phosphorylase activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1590793" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Asai, K., Nakanishi, K., Isobe, I., Eksioglu, Y. Z., Hirano, A., Hama, K., Miyamoto, T., Kato, T. <strong>Neurotrophic action of gliostatin on cortical neurons: identity of gliostatin and platelet-derived endothelial cell growth factor.</strong> J. Biol. Chem. 267: 20311-20316, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1400349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1400349</a>]" pmid="1400349">Asai et al. (1992)</a> found that gliostatin and PDECGF shared growth inhibition of glial cells and growth promotion of endothelial cells, suggesting that both factors evoke the biologic actions through an identical receptor on each cell surface. <a href="#1" class="mim-tip-reference" title="Asai, K., Nakanishi, K., Isobe, I., Eksioglu, Y. Z., Hirano, A., Hama, K., Miyamoto, T., Kato, T. <strong>Neurotrophic action of gliostatin on cortical neurons: identity of gliostatin and platelet-derived endothelial cell growth factor.</strong> J. Biol. Chem. 267: 20311-20316, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1400349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1400349</a>]" pmid="1400349">Asai et al. (1992)</a> also demonstrated a novel neurotrophic action of gliostatin/PDECGF toward embryonic rat cortical neurons in culture. These data indicated that gliostatin/PDECGF may play important roles in development and regeneration of the central nervous system, and may also involve the induction of angiogenesis for the formation of blood-brain barrier. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1400349" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Griffiths, L., Stratford, I. J. <strong>Platelet-derived endothelial cell growth factor thymidine phosphorylase in tumour growth and response to therapy.</strong> Brit. J. Cancer 76: 689-693, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9310231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9310231</a>] [<a href="https://doi.org/10.1038/bjc.1997.447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9310231">Griffiths and Stratford (1997)</a> reviewed the major functions of PDECGF. In addition to being chemotactic for endothelial cells in vitro and angiogenic in vivo, it promotes neuronal survival (gliostatin), and catalyzes the reversible phosphorylation of thymidine to thymine (thymidine phosphorylase). Thymidine phosphorylase activity is critical for angiogenic activity. The PDECGF protein is highly expressed in tumors compared with most normal tissues and has been correlated with tumor growth, invasion, and metastasis in clinical studies. In addition, thymidine phosphorylase activity has been found to be a major determinant of the toxicity of 5-fluorouracil and its prodrugs, which are used clinically as anticancer agents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9310231" 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 12 probands with mitochondrial DNA depletion syndrome-1 (MTDPS1; <a href="/entry/603041">603041</a>), which manifests as mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), <a href="#11" class="mim-tip-reference" title="Nishino, I., Spinazzola, A., Hirano, M. <strong>Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder.</strong> Science 283: 689-692, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9924029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9924029</a>] [<a href="https://doi.org/10.1126/science.283.5402.689" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9924029">Nishino et al. (1999)</a> identified 10 homozygous or compound heterozygous mutations in the TYMP gene (see, e.g., <a href="#0001">131222.0001</a>-<a href="#0008">131222.0008</a>). TYMP activity in leukocytes from these patients was less than 5% of controls, indicating that loss-of-function mutations in TYMP cause the disorder. Studies of skeletal muscle showed multiple mitochondrial DNA deletions in 7 of 9 patients tested. <a href="#11" class="mim-tip-reference" title="Nishino, I., Spinazzola, A., Hirano, M. <strong>Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder.</strong> Science 283: 689-692, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9924029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9924029</a>] [<a href="https://doi.org/10.1126/science.283.5402.689" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9924029">Nishino et al. (1999)</a> noted that TYMP is expressed at only low levels in skeletal muscle, suggesting that these mtDNA deletions may be an epiphenomenon. The authors hypothesized that aberrant thymidine metabolism leads to impaired replication or maintenance of mtDNA, causing mtDNA depletion, deletion, or both. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9924029" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with a classic MNGIE clinical presentation but without skeletal muscle involvement at the morphologic, enzymatic, or mtDNA level, <a href="#16" class="mim-tip-reference" title="Szigeti, K., Wong, L.-J. C., Perng, C.-L., Saifi, G. M., Eldin, K., Adesina, A. M., Cass, D. L., Hirano, M., Lupski, J. R., Scaglia, F. <strong>MNGIE with lack of skeletal muscle involvement and a novel TP splice site mutation.</strong> J. Med. Genet. 41: 125-129, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14757860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14757860</a>] [<a href="https://doi.org/10.1136/jmg.2003.013789" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14757860">Szigeti et al. (2004)</a> identified a homozygous splice site mutation in the TYMP gene (<a href="#0010">131222.0010</a>). <a href="#16" class="mim-tip-reference" title="Szigeti, K., Wong, L.-J. C., Perng, C.-L., Saifi, G. M., Eldin, K., Adesina, A. M., Cass, D. L., Hirano, M., Lupski, J. R., Scaglia, F. <strong>MNGIE with lack of skeletal muscle involvement and a novel TP splice site mutation.</strong> J. Med. Genet. 41: 125-129, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14757860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14757860</a>] [<a href="https://doi.org/10.1136/jmg.2003.013789" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14757860">Szigeti et al. (2004)</a> concluded that it is important to examine the most significantly affected tissue and to measure thymidine phosphorylase activity and plasma thymidine to arrive at an accurate diagnosis in this condition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14757860" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Hirano, M., Lagier-Tourenne, C., Valentino, M. L., Marti, R., Nishigaki, Y. <strong>Thymidine phosphorylase mutations cause instability of mitochondrial DNA.</strong> Gene 354: 152-156, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15975738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15975738</a>] [<a href="https://doi.org/10.1016/j.gene.2005.04.041" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15975738">Hirano et al. (2005)</a> demonstrated that TYMP activity was decreased to about 1.5% of control values in leukocytes derived from patients with MNGIE due to TYMP mutations. Asymptomatic heterozygous mutation carriers had about 35% residual TYMP activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15975738" 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="#9" class="mim-tip-reference" title="Marti, R., Verschuuren, J. J. G. M., Buchman, A., Hirano, I., Tadesse, S., van Kuilenburg, A. B. P., van Gennip, A. H., Poorthuis, B. J. H. M., Hirano, M. <strong>Late-onset MNGIE due to partial loss of thymidine phosphorylase activity.</strong> Ann. Neurol. 58: 649-652, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16178026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16178026</a>] [<a href="https://doi.org/10.1002/ana.20615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16178026">Marti et al. (2005)</a> reported 3 unrelated patients with late-onset MNGIE confirmed by the identification of TYMP mutations (<a href="#0011">131222.0011</a>-<a href="#0014">131222.0014</a>). The patients developed symptoms at ages 40 to 52 years, later than that observed in patients with typical MNGIE. Plasma deoxythymidine levels were mildly elevated, ranging from 0.4 to 1.4 microM, indicating that even low levels are pathogenic. Biochemical analysis showed 9 to 16% residual TYMP activity, which likely accounted for the later onset in these patients. Unaffected heterozygous mutation carriers had 26 to 35% residual TYMP activity, suggesting a minimal level required to prevent disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16178026" 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>Murine uridine phosphorylate, unlike human UPP1 (<a href="/entry/191730">191730</a>), cleaves thymidine as well as uridine. To knock out Tymp activity in mice, <a href="#5" class="mim-tip-reference" title="Haraguchi, M., Tsujimoto, H., Fukushima, M., Higuchi, I., Kuribayashi, H., Utsumi, H., Nakayama, A., Hashizume, Y., Hirato, J., Yoshida, H., Hara, H., Hamano, S., and 17 others. <strong>Targeted deletion of both thymidine phosphorylase and uridine phosphorylase and consequent disorders in mice.</strong> Molec. Cell. Biol. 22: 5212-5221, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12077348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12077348</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12077348[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/10.1128/MCB.22.14.5212-5221.2002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12077348">Haraguchi et al. (2002)</a> created Upp1/Tymp double-knockout mice. They found no alterations in mitochondrial DNA or pathologic changes in the muscles of double-knockout mice, even when these mice were fed thymidine for 7 months. However, they found intense lesions in the brain on T2-weighted MRI, and axonal edema by electron microscopic study of the brain of double-knockout mice. <a href="#5" class="mim-tip-reference" title="Haraguchi, M., Tsujimoto, H., Fukushima, M., Higuchi, I., Kuribayashi, H., Utsumi, H., Nakayama, A., Hashizume, Y., Hirato, J., Yoshida, H., Hara, H., Hamano, S., and 17 others. <strong>Targeted deletion of both thymidine phosphorylase and uridine phosphorylase and consequent disorders in mice.</strong> Molec. Cell. Biol. 22: 5212-5221, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12077348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12077348</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12077348[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/10.1128/MCB.22.14.5212-5221.2002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12077348">Haraguchi et al. (2002)</a> concluded that inhibition of TYMP activity causes elevation of pyrimidine levels in plasma and consequent axonal swelling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12077348" 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>Replication and repair of DNA require equilibrated pools of deoxynucleoside triphosphate precursors. <a href="#8" class="mim-tip-reference" title="Lopez, L. C., Akman, H. O., Garcia-Cazorla, A., Dorado, B., Marti, R., Nishino, I., Tadesse, S., Pizzorno, G., Shungu, D., Bonilla, E., Tanji, K., Hirano, M. <strong>Unbalanced deoxynucleotide pools cause mitochondrial DNA instability in thymidine phosphorylase-deficient mice.</strong> Hum. Molec. Genet. 18: 714-722, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19028666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19028666</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19028666[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn401" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19028666">Lopez et al. (2009)</a> generated Tymp and Upp1 double-knockout mice, which showed severe Tymp deficiency, increased thymidine and deoxyuridine in tissues, and elevated mitochondrial deoxythymidine triphosphate. As consequences of the nucleotide pool imbalances, brains of mutant mice developed partial depletion of mtDNA, deficiencies of respiratory chain complexes, and encephalopathy. These findings largely account for the pathogenesis of MNGIE, the first inherited human disorder of nucleoside metabolism associated with somatic DNA instability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19028666" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=131222[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<p>In patients with mitochondrial DNA depletion syndrome-1 (MTDPS1; <a href="/entry/603041">603041</a>), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), <a href="#11" class="mim-tip-reference" title="Nishino, I., Spinazzola, A., Hirano, M. <strong>Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder.</strong> Science 283: 689-692, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9924029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9924029</a>] [<a href="https://doi.org/10.1126/science.283.5402.689" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9924029">Nishino et al. (1999)</a> identified a 3371A-C transversion in exon 7 of the ECGF1 gene, resulting in a glu289-to-ala (E289A) substitution. This mutation was seen in homozygosity in an Ashkenazi Jewish patient and in compound heterozygosity in 4 other patients of German American (<a href="#0002">131222.0002</a>), German (<a href="#0006">131222.0006</a>), English (<a href="#0008">131222.0008</a>), and European American ancestry. The mutation was associated with mitochondrial deletions in skeletal muscle, presumably resulting from mtDNA depletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9924029" 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 patient with mitochondrial DNA depletion syndrome-1 (MTDPS1; <a href="/entry/603041">603041</a>), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), <a href="#11" class="mim-tip-reference" title="Nishino, I., Spinazzola, A., Hirano, M. <strong>Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder.</strong> Science 283: 689-692, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9924029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9924029</a>] [<a href="https://doi.org/10.1126/science.283.5402.689" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9924029">Nishino et al. (1999)</a> identified compound heterozygosity for 2 mutations in the TYMP gene: E289A (<a href="#0001">131222.0001</a>), and a 1504T-C transition in intron 4 that altered the splice donor site. When assayed by RT-PCR in leukocytes, the latter mutation caused skipping of exon 4. This would lead to loss of 33 amino acids in the mature protein and deletion of the thymidine phosphorylase consensus. The mutations were associated with mitochondrial deletions in skeletal muscle, presumably resulting from mtDNA depletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9924029" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)</strong>
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TYMP, GLY145ARG
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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> rs121913037 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913037;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/rs121913037?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=rs121913037" 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=rs121913037" 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=RCV000018135 OR RCV001049989 OR RCV001276278" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018135, RCV001049989, RCV001276278" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018135...</a>
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<p>In patients with mitochondrial DNA depletion syndrome-1 (MTDPS1; <a href="/entry/603041">603041</a>), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), <a href="#11" class="mim-tip-reference" title="Nishino, I., Spinazzola, A., Hirano, M. <strong>Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder.</strong> Science 283: 689-692, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9924029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9924029</a>] [<a href="https://doi.org/10.1126/science.283.5402.689" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9924029">Nishino et al. (1999)</a> identified a 1419A-C transversion in exon 4 of the ECGF1 gene, causing a gly145-to-arg (G145R) substitution. The mutation was found in homozygosity in 2 Puerto Rican and 1 Israeli patient. The mutation, in the region of the thymidine phosphorylase consensus, was associated with multiple mtDNA deletions in skeletal muscle, presumably resulting from mtDNA depletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9924029" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<span class="mim-font">
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<strong>.0004 MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)</strong>
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TYMP, LYS222ARG
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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> rs149977726 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs149977726;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/rs149977726?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=rs149977726" 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=rs149977726" 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=RCV000018136 OR RCV000497545 OR RCV001831582" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018136, RCV000497545, RCV001831582" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018136...</a>
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<p><a href="#12" class="mim-tip-reference" title="Nishino, I., Spinazzola, A., Papadimitriou, A., Hammans, S., Steiner, I., Hahn, C. D., Connolly, A. M., Verloes, A., Guimaraes, J., Maillard, I., Hamano, H., Donati, M. A., and 13 others. <strong>Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations.</strong> Ann. Neurol. 47: 792-800, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10852545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10852545</a>]" pmid="10852545">Nishino et al. (2000)</a> reported an African American patient with mitochondrial DNA depletion syndrome-1 (MTDPS1; <a href="/entry/603041">603041</a>), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), who was compound heterozygous for 2 mutations in the TYMP gene: a 2744A-G transition, resulting in a lys222-to-arg (L222R) substitution, and a 1-bp insertion (4196insC; <a href="#0005">131222.0005</a>). This patient had previously been described by <a href="#11" class="mim-tip-reference" title="Nishino, I., Spinazzola, A., Hirano, M. <strong>Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder.</strong> Science 283: 689-692, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9924029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9924029</a>] [<a href="https://doi.org/10.1126/science.283.5402.689" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9924029">Nishino et al. (1999)</a>, who found that the missense mutation disrupted the thymidine phosphorylase phosphate binding site and that the mutations were associated with multiple mtDNA deletions in skeletal muscle, presumably resulting from mtDNA depletion. (<a href="#11" class="mim-tip-reference" title="Nishino, I., Spinazzola, A., Hirano, M. <strong>Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder.</strong> Science 283: 689-692, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9924029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9924029</a>] [<a href="https://doi.org/10.1126/science.283.5402.689" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9924029">Nishino et al. (1999)</a> erroneously stated that the missense mutation in this patient, who was described as Jamaican, was a lys222-to-ser (K222S) substitution.) <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9924029+10852545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0005" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0005 MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)</strong>
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</h4>
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TYMP, 1-BP INS, 4196C
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs786205097 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205097;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=rs786205097" 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=rs786205097" 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=RCV000018137" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018137" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018137</a>
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<span class="mim-text-font">
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<p>For discussion of the 1-bp insertion in the TYMP gene (4196insC) that was found in compound heterozygous state in a patient with mitochondrial DNA depletion syndrome-1 (MTDPS1; <a href="/entry/603041">603041</a>), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), by <a href="#12" class="mim-tip-reference" title="Nishino, I., Spinazzola, A., Papadimitriou, A., Hammans, S., Steiner, I., Hahn, C. D., Connolly, A. M., Verloes, A., Guimaraes, J., Maillard, I., Hamano, H., Donati, M. A., and 13 others. <strong>Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations.</strong> Ann. Neurol. 47: 792-800, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10852545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10852545</a>]" pmid="10852545">Nishino et al. (2000)</a> and <a href="#11" class="mim-tip-reference" title="Nishino, I., Spinazzola, A., Hirano, M. <strong>Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder.</strong> Science 283: 689-692, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9924029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9924029</a>] [<a href="https://doi.org/10.1126/science.283.5402.689" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9924029">Nishino et al. (1999)</a>, see <a href="#0004">131222.0004</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9924029+10852545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0006" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0006 MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)</strong>
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TYMP, IVS8AS, 3867G-C
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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> rs797044455 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797044455;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/rs797044455?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=rs797044455" 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=rs797044455" 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=RCV000018138" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018138" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018138</a>
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<p>In a patient with mitochondrial DNA depletion syndrome-1 (MTDPS1; <a href="/entry/603041">603041</a>), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), <a href="#11" class="mim-tip-reference" title="Nishino, I., Spinazzola, A., Hirano, M. <strong>Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder.</strong> Science 283: 689-692, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9924029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9924029</a>] [<a href="https://doi.org/10.1126/science.283.5402.689" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9924029">Nishino et al. (1999)</a> identified compound heterozygosity for 2 mutations in the TYMP gene: E289A (<a href="#0001">131222.0001</a>), and a 3867G-C transversion that disrupted the splice acceptor site of intron 8, leading to skipping of exon 9 and disruption of the leucine zipper motif. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9924029" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0007" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0007 MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)</strong>
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TYMP, 6-BP DEL
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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> rs786205098 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205098;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/rs786205098?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=rs786205098" 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=rs786205098" 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=RCV000018139" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018139" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018139</a>
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<p>In a patient with mitochondrial DNA depletion syndrome-1 (MTDPS1; <a href="/entry/603041">603041</a>), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), <a href="#11" class="mim-tip-reference" title="Nishino, I., Spinazzola, A., Hirano, M. <strong>Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder.</strong> Science 283: 689-692, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9924029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9924029</a>] [<a href="https://doi.org/10.1126/science.283.5402.689" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9924029">Nishino et al. (1999)</a> identified a homozygous 6-bp deletion in exon 9 of the ECGF1 gene that resulted in loss of leucine-397 and alanine-398. Although neither amino acid is strictly conserved, the authors suggested that their loss could alter the structure and enzymatic activity of the thymidine phosphorylase protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9924029" 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 MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)</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> rs121913038 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913038;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/rs121913038?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=rs121913038" 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=rs121913038" 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=RCV000018140 OR RCV001052862 OR RCV001826476" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018140, RCV001052862, RCV001826476" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018140...</a>
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<p>In patients with mitochondrial DNA depletion syndrome-1 (MTDPS1; <a href="/entry/603041">603041</a>), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), <a href="#11" class="mim-tip-reference" title="Nishino, I., Spinazzola, A., Hirano, M. <strong>Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder.</strong> Science 283: 689-692, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9924029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9924029</a>] [<a href="https://doi.org/10.1126/science.283.5402.689" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9924029">Nishino et al. (1999)</a> identified a 1443G-A transition in the ECGF1 gene, resulting in a gly153-to-ser (G153S) substitution. The mutation was identified in homozygosity in an English patient and in compound heterozygosity with the E289A mutation (<a href="#0001">131222.0001</a>) in another English and 1 European American patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9924029" 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 MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)</strong>
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TYMP, ARG44GLN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28931613 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28931613;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=rs28931613" 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=rs28931613" 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=RCV000018141 OR RCV002513094" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018141, RCV002513094" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018141...</a>
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<p>In 2 Spanish sisters with mitochondrial DNA depletion syndrome-1 (MTDPS1; <a href="/entry/603041">603041</a>), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), <a href="#2" class="mim-tip-reference" title="Gamez, J., Ferreiro, C., Accarino, M. L., Guarner, L., Tadesse, S., Marti, R. A., Andreu, A. L., Raguer, N., Cervera, C., Hirano, M. <strong>Phenotypic variability in a Spanish family with MNGIE.</strong> Neurology 59: 455-457, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12177387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12177387</a>] [<a href="https://doi.org/10.1212/wnl.59.3.455" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12177387">Gamez et al. (2002)</a> identified a homozygous 435G-A transition in the ECGF1 gene, resulting in an arg44-to-gln (R44Q) substitution in the mature protein. The authors noted that arg44 is located in the N-terminal domain of the protein and that the substitution of a positively charged (arg) by an uncharged (gln) amino acid could account for loss of enzyme activity in the 2 affected sisters. The mother and an unaffected sister were heterozygous for the mutation. Clinically, the affected sisters presented with variable phenotypes: one had predominantly gastrointestinal symptoms and the other had ophthalmoparesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12177387" 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 MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)</strong>
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TYMP, IVS1AS, G-C, -1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs767245071 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs767245071;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/rs767245071?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=rs767245071" 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=rs767245071" 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=RCV000018142 OR RCV000599020 OR RCV001276279" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018142, RCV000599020, RCV001276279" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018142...</a>
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<p>In a patient with mitochondrial DNA depletion syndrome-1 (MTDPS1; <a href="/entry/603041">603041</a>), manifest as classic mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) but without skeletal muscle involvement at the morphologic, enzymatic, or mtDNA level, <a href="#16" class="mim-tip-reference" title="Szigeti, K., Wong, L.-J. C., Perng, C.-L., Saifi, G. M., Eldin, K., Adesina, A. M., Cass, D. L., Hirano, M., Lupski, J. R., Scaglia, F. <strong>MNGIE with lack of skeletal muscle involvement and a novel TP splice site mutation.</strong> J. Med. Genet. 41: 125-129, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14757860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14757860</a>] [<a href="https://doi.org/10.1136/jmg.2003.013789" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14757860">Szigeti et al. (2004)</a> identified a homozygous G-to-C transversion at the splice acceptor site of exon 2 of the ECGF1 gene. The mutation resulted in skipping of exon 2 and loss of function of the protein, which was confirmed by the markedly reduced enzyme activity measured in peripheral blood. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14757860" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)</strong>
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TYMP, VAL208MET
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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> rs121913039 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913039;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/rs121913039?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=rs121913039" 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=rs121913039" 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=RCV000018143 OR RCV000199543" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018143, RCV000199543" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018143...</a>
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<p>In 2 unrelated women with mitochondrial DNA depletion syndrome-1 (MTDPS1; <a href="/entry/603041">603041</a>), manifest as late-onset mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), <a href="#9" class="mim-tip-reference" title="Marti, R., Verschuuren, J. J. G. M., Buchman, A., Hirano, I., Tadesse, S., van Kuilenburg, A. B. P., van Gennip, A. H., Poorthuis, B. J. H. M., Hirano, M. <strong>Late-onset MNGIE due to partial loss of thymidine phosphorylase activity.</strong> Ann. Neurol. 58: 649-652, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16178026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16178026</a>] [<a href="https://doi.org/10.1002/ana.20615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16178026">Marti et al. (2005)</a> identified compound heterozygosity for 2 mutations in the ECGF1 gene. Both patients had a 2398G-A transition, resulting in a val208-to-met (V208M) substitution. In addition, 1 patient had a 3535G-C transversion, resulting in a gly311-to-arg substitution (G311R; <a href="#0012">131222.0012</a>), and the other had a 2381G-C transversion, resulting in an arg202-to-thr substitution (R202T; <a href="#0013">131222.0013</a>). The patients had onset of gastrointestinal symptoms at age 42 and 40 years, respectively. Biochemical analysis showed 15 to 16% residual enzyme activity in both patients, which likely accounted for the later onset. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16178026" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)</strong>
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TYMP, GLY311ARG
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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> rs121913040 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913040;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/rs121913040?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=rs121913040" 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=rs121913040" 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=RCV000018144" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018144" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018144</a>
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<p>For discussion of the gly311-to-arg (G311R) mutation in the TYMP gene that was found in compound heterozygous state in patients with mitochondrial DNA depletion syndrome-1 (MTDPS1; <a href="/entry/603041">603041</a>), manifest as late-onset mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), by <a href="#9" class="mim-tip-reference" title="Marti, R., Verschuuren, J. J. G. M., Buchman, A., Hirano, I., Tadesse, S., van Kuilenburg, A. B. P., van Gennip, A. H., Poorthuis, B. J. H. M., Hirano, M. <strong>Late-onset MNGIE due to partial loss of thymidine phosphorylase activity.</strong> Ann. Neurol. 58: 649-652, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16178026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16178026</a>] [<a href="https://doi.org/10.1002/ana.20615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16178026">Marti et al. (2005)</a>, see <a href="#0011">131222.0011</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16178026" 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>.0013 MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)</strong>
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TYMP, ARG202THR
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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> rs121913041 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913041;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/rs121913041?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=rs121913041" 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=rs121913041" 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=RCV000018145 OR RCV003228895" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018145, RCV003228895" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018145...</a>
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<p>For discussion of the arg202-to-thr (R202T) mutation in the TYMP gene that was found in compound heterozygous state in patients with mitochondrial DNA depletion syndrome-1 (MTDPS1; <a href="/entry/603041">603041</a>), manifest as late-onset mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), by <a href="#9" class="mim-tip-reference" title="Marti, R., Verschuuren, J. J. G. M., Buchman, A., Hirano, I., Tadesse, S., van Kuilenburg, A. B. P., van Gennip, A. H., Poorthuis, B. J. H. M., Hirano, M. <strong>Late-onset MNGIE due to partial loss of thymidine phosphorylase activity.</strong> Ann. Neurol. 58: 649-652, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16178026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16178026</a>] [<a href="https://doi.org/10.1002/ana.20615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16178026">Marti et al. (2005)</a>, see <a href="#0011">131222.0011</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16178026" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0014 MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)</strong>
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TYMP, LEU285PRO
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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> rs121913042 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913042;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/rs121913042?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=rs121913042" 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=rs121913042" 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=RCV000018146 OR RCV003330395 OR RCV003556042" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018146, RCV003330395, RCV003556042" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018146...</a>
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<span class="mim-text-font">
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<p>In an African American man with mitochondrial DNA depletion syndrome-1 (MTDPS1; <a href="/entry/603041">603041</a>) manifest as late-onset mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), <a href="#9" class="mim-tip-reference" title="Marti, R., Verschuuren, J. J. G. M., Buchman, A., Hirano, I., Tadesse, S., van Kuilenburg, A. B. P., van Gennip, A. H., Poorthuis, B. J. H. M., Hirano, M. <strong>Late-onset MNGIE due to partial loss of thymidine phosphorylase activity.</strong> Ann. Neurol. 58: 649-652, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16178026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16178026</a>] [<a href="https://doi.org/10.1002/ana.20615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16178026">Marti et al. (2005)</a> identified compound heterozygosity for 2 mutations in the ECGF1 gene: a 3359T-C transition, resulting in a leu285-to-pro (L285P) substitution, and a G153S mutation (<a href="#0008">131222.0008</a>). The patient had onset of lower gastrointestinal bleeding at age 52 years, followed by peripheral neuropathy, external ophthalmoplegia, and leukoencephalopathy. Biochemical analysis showed 9 to 13% residual enzyme activity, which likely accounted for the later onset. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16178026" 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 href="https://doi.org/10.1212/wnl.59.3.455" target="_blank">Full Text</a>]
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Griffiths, L., Stratford, I. J.
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[<a href="https://doi.org/10.1038/bjc.1997.447" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2005900/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2005900</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2005900" 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/10.1128/mcb.11.4.2125-2132.1991" target="_blank">Full Text</a>]
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Haraguchi, M., Tsujimoto, H., Fukushima, M., Higuchi, I., Kuribayashi, H., Utsumi, H., Nakayama, A., Hashizume, Y., Hirato, J., Yoshida, H., Hara, H., Hamano, S., and 17 others.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12077348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12077348</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12077348[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=12077348" 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/10.1128/MCB.22.14.5212-5221.2002" target="_blank">Full Text</a>]
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Lopez, L. C., Akman, H. O., Garcia-Cazorla, A., Dorado, B., Marti, R., Nishino, I., Tadesse, S., Pizzorno, G., Shungu, D., Bonilla, E., Tanji, K., Hirano, M.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19028666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19028666</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19028666[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=19028666" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddn401" target="_blank">Full Text</a>]
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<li>
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<a id="9" class="mim-anchor"></a>
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<a id="Marti2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Marti, R., Verschuuren, J. J. G. M., Buchman, A., Hirano, I., Tadesse, S., van Kuilenburg, A. B. P., van Gennip, A. H., Poorthuis, B. J. H. M., Hirano, M.
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<strong>Late-onset MNGIE due to partial loss of thymidine phosphorylase activity.</strong>
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Ann. Neurol. 58: 649-652, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16178026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16178026</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16178026" 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/ana.20615" 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="10" class="mim-anchor"></a>
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<a id="Matsukawa1996" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
|
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Matsukawa, K., Moriyama, A., Kawai, Y., Asai, K., Kato, T.
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<strong>Tissue distribution of human gliostatin/platelet-derived endothelial cell growth factor (PD-ECGF) and its drug-induced expression.</strong>
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Biochim. Biophys. Acta 1314: 71-82, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8972720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8972720</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8972720" 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/s0167-4889(96)00078-x" 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="11" class="mim-anchor"></a>
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<a id="Nishino1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Nishino, I., Spinazzola, A., Hirano, M.
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|
<strong>Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder.</strong>
|
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Science 283: 689-692, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9924029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9924029</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9924029" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.283.5402.689" 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="12" class="mim-anchor"></a>
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<a id="Nishino2000" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
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Nishino, I., Spinazzola, A., Papadimitriou, A., Hammans, S., Steiner, I., Hahn, C. D., Connolly, A. M., Verloes, A., Guimaraes, J., Maillard, I., Hamano, H., Donati, M. A., and 13 others.
|
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<strong>Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations.</strong>
|
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Ann. Neurol. 47: 792-800, 2000.
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|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10852545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10852545</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10852545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="Stenman1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Stenman, G., Sahlin, P., Dumanski, J. P., Hagiwara, K., Ishikawa, F., Miyazono, K., Collins, V. P., Heldin, C.-H.
|
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<strong>Regional localization of the human platelet-derived endothelial cell growth factor (ECGF1) gene to chromosome 22q13.</strong>
|
|
Cytogenet. Cell Genet. 59: 22-23, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1733667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1733667</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1733667" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1159/000133191" 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="14" class="mim-anchor"></a>
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<a id="Stenman1991" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Stenman, G., Sahlin, P., Hagiwara, K., Dumanski, J., Collins, V., Heldin, C.-H.
|
|
<strong>Mapping of the human platelet-derived endothelial cell growth factor (PD-ECGF) gene to chromosome 22q13. (Abstract)</strong>
|
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Cytogenet. Cell Genet. 58: 2051 only, 1991.
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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="15" class="mim-anchor"></a>
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<a id="Suomalainen2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Suomalainen, A., Isohanni, P.
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<strong>Mitochondrial DNA depletion syndromes: many genes, common mechanisms.</strong>
|
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Neuromusc. Disord. 20: 429-437, 2010.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20444604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20444604</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20444604" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.nmd.2010.03.017" 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="16" class="mim-anchor"></a>
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<a id="Szigeti2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Szigeti, K., Wong, L.-J. C., Perng, C.-L., Saifi, G. M., Eldin, K., Adesina, A. M., Cass, D. L., Hirano, M., Lupski, J. R., Scaglia, F.
|
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<strong>MNGIE with lack of skeletal muscle involvement and a novel TP splice site mutation.</strong>
|
|
J. Med. Genet. 41: 125-129, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14757860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14757860</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14757860" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.2003.013789" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="17" class="mim-anchor"></a>
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<a id="Usuki1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Usuki, K., Saras, J., Waltenberger, J., Miyazono, K., Pierce, G., Thomason, A., Heldin, C.-H.
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<strong>Platelet-derived endothelial cell growth factor has thymidine phosphorylase activity.</strong>
|
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Biochem. Biophys. Res. Commun. 184: 1311-1316, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1590793/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1590793</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1590793" 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/s0006-291x(05)80025-7" 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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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 12/9/2010
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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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George E. Tiller - updated : 8/10/2009<br>Patricia A. Hartz - updated : 8/30/2006<br>Cassandra L. Kniffin - updated : 12/1/2005<br>Marla J. F. O'Neill - updated : 9/20/2004<br>Victor A. McKusick - updated : 5/2/2003<br>Cassandra L. Kniffin - updated : 10/3/2002<br>Ada Hamosh - updated : 1/28/1999
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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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Victor A. McKusick : 8/6/1991
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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 : 08/15/2024
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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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alopez : 04/30/2015<br>mcolton : 4/17/2015<br>carol : 1/27/2014<br>terry : 1/4/2011<br>carol : 12/16/2010<br>ckniffin : 12/9/2010<br>wwang : 8/21/2009<br>terry : 8/10/2009<br>wwang : 9/5/2006<br>terry : 8/30/2006<br>wwang : 12/5/2005<br>ckniffin : 12/1/2005<br>tkritzer : 9/20/2004<br>cwells : 5/6/2003<br>terry : 5/2/2003<br>carol : 10/21/2002<br>ckniffin : 10/3/2002<br>alopez : 1/29/1999<br>alopez : 1/28/1999<br>alopez : 1/28/1999<br>mimadm : 4/18/1994<br>supermim : 3/16/1992<br>carol : 2/21/1992<br>carol : 2/16/1992<br>carol : 1/31/1992<br>carol : 8/20/1991
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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> 131222
|
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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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|
|
THYMIDINE PHOSPHORYLASE; TYMP
|
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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">
|
|
<em>Alternative titles; symbols</em>
|
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</span>
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</p>
|
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
TP<br />
|
|
ENDOTHELIAL CELL GROWTH FACTOR, PLATELET-DERIVED; ECGF; ECGF1<br />
|
|
PLATELET-DERIVED ENDOTHELIAL CELL GROWTH FACTOR; PDECGF<br />
|
|
GLIOSTATIN
|
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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">
|
|
<strong><em>HGNC Approved Gene Symbol: TYMP</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>
|
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<em>
|
|
Cytogenetic location: 22q13.33
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 22:50,525,752-50,530,085 </span>
|
|
</em>
|
|
</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">
|
|
<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>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
|
<th>
|
|
Phenotype
|
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</th>
|
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
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</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
22q13.33
|
|
</span>
|
|
</td>
|
|
|
|
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<td>
|
|
<span class="mim-font">
|
|
Mitochondrial DNA depletion syndrome 1 (MNGIE type)
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
603041
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
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|
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</tr>
|
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|
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</tbody>
|
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</table>
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</div>
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</div>
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<div>
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<br />
|
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</div>
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<div>
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|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
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</h4>
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>The TYMP gene encodes thymidine phosphorylase (EC 2.4.2.4), a cytosolic enzyme that catalyzes the phosphorylation of thymidine or deoxyuridine to thymine or uracil, and is thus essential for the nucleotide salvage pathway (review by Suomalainen and Isohanni, 2010). The protein product was originally identified as platelet-derived endothelial cell growth factor (PDECGF), an angiogenic factor distinct from the previously described endothelial cell mitogens of the fibroblast growth factor family (Ishikawa et al., 1989). PDECGF is stored in platelets as a 45-kD single polypeptide chain and has a highly restricted target cell specificity acting only on endothelial cells. It promotes angiogenesis in vivo, and stimulates the in vitro growth of a variety of endothelial cells. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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|
<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Ishikawa et al. (1989) isolated clones corresponding to the PDECGF gene from a placenta cDNA library. The deduced 482-residue protein had a molecular mass of 49.97 kD; Northern blot analysis detected a 1.8-kb mRNA transcript. Expression studies showed that the clone had growth-promoting activity for porcine aortic endothelial cells and a chemotactic effect for bovine endothelial cells, as well as angiogenic activity in mouse tumors. The findings confirmed that PDECGF acts as a potent angiogenic factor and likely plays a role in the maintenance of blood vessels. </p><p>Usuki et al. (1992) found that the PDECGF protein shared 39.2% amino acid sequence similarity over a 439-amino acid region with thymidine phosphorylase in E. coli. They found that the enzyme occurs as a 90-kD homodimer, similar to other thymidine phosphorylases. </p><p>Asai et al. (1992) found that gliostatin, a homodimeric structure of two 50-kD subunits, was identical to PDECGF. </p><p>Matsukawa et al. (1996) found ubiquitous expression of the PDECGF gene in various human tissues and organs, with relatively high levels in the digestive system, including esophagus and rectum, as well as in brain, spleen, bladder and lung. There was little or no expression in gallbladder, aorta, muscle, fat, and kidney. In addition, most human tumor cell lines showed 4- or 5-fold higher expression of the protein than normal tissue. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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|
<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Hagiwara et al. (1991) determined that the PDECGF gene contains 10 exons spanning more than 4.3 kb. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using an ECGF1 cDNA probe, Stenman et al. (1991, 1992) assigned the ECGF1 gene to chromosome 22 by analysis of its segregation in a panel of human/rodent somatic cell hybrids. By in situ hybridization, they sublocalized the gene to 22q13. The ECGF1 gene is in the same region as the PDGFB gene (190040) but is located distal to the 22q13 breakpoint in hybrid 1/22AM27, while PDGFB is proximal to this breakpoint. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Usuki et al. (1992) demonstrated that PDECGF has thymidine phosphorylase activity. </p><p>Asai et al. (1992) found that gliostatin and PDECGF shared growth inhibition of glial cells and growth promotion of endothelial cells, suggesting that both factors evoke the biologic actions through an identical receptor on each cell surface. Asai et al. (1992) also demonstrated a novel neurotrophic action of gliostatin/PDECGF toward embryonic rat cortical neurons in culture. These data indicated that gliostatin/PDECGF may play important roles in development and regeneration of the central nervous system, and may also involve the induction of angiogenesis for the formation of blood-brain barrier. </p><p>Griffiths and Stratford (1997) reviewed the major functions of PDECGF. In addition to being chemotactic for endothelial cells in vitro and angiogenic in vivo, it promotes neuronal survival (gliostatin), and catalyzes the reversible phosphorylation of thymidine to thymine (thymidine phosphorylase). Thymidine phosphorylase activity is critical for angiogenic activity. The PDECGF protein is highly expressed in tumors compared with most normal tissues and has been correlated with tumor growth, invasion, and metastasis in clinical studies. In addition, thymidine phosphorylase activity has been found to be a major determinant of the toxicity of 5-fluorouracil and its prodrugs, which are used clinically as anticancer agents. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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|
<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In 12 probands with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), which manifests as mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), Nishino et al. (1999) identified 10 homozygous or compound heterozygous mutations in the TYMP gene (see, e.g., 131222.0001-131222.0008). TYMP activity in leukocytes from these patients was less than 5% of controls, indicating that loss-of-function mutations in TYMP cause the disorder. Studies of skeletal muscle showed multiple mitochondrial DNA deletions in 7 of 9 patients tested. Nishino et al. (1999) noted that TYMP is expressed at only low levels in skeletal muscle, suggesting that these mtDNA deletions may be an epiphenomenon. The authors hypothesized that aberrant thymidine metabolism leads to impaired replication or maintenance of mtDNA, causing mtDNA depletion, deletion, or both. </p><p>In a patient with a classic MNGIE clinical presentation but without skeletal muscle involvement at the morphologic, enzymatic, or mtDNA level, Szigeti et al. (2004) identified a homozygous splice site mutation in the TYMP gene (131222.0010). Szigeti et al. (2004) concluded that it is important to examine the most significantly affected tissue and to measure thymidine phosphorylase activity and plasma thymidine to arrive at an accurate diagnosis in this condition. </p><p>Hirano et al. (2005) demonstrated that TYMP activity was decreased to about 1.5% of control values in leukocytes derived from patients with MNGIE due to TYMP mutations. Asymptomatic heterozygous mutation carriers had about 35% residual TYMP activity. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>Genotype/Phenotype Correlations</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>Marti et al. (2005) reported 3 unrelated patients with late-onset MNGIE confirmed by the identification of TYMP mutations (131222.0011-131222.0014). The patients developed symptoms at ages 40 to 52 years, later than that observed in patients with typical MNGIE. Plasma deoxythymidine levels were mildly elevated, ranging from 0.4 to 1.4 microM, indicating that even low levels are pathogenic. Biochemical analysis showed 9 to 16% residual TYMP activity, which likely accounted for the later onset in these patients. Unaffected heterozygous mutation carriers had 26 to 35% residual TYMP activity, suggesting a minimal level required to prevent disease. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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|
<p>Murine uridine phosphorylate, unlike human UPP1 (191730), cleaves thymidine as well as uridine. To knock out Tymp activity in mice, Haraguchi et al. (2002) created Upp1/Tymp double-knockout mice. They found no alterations in mitochondrial DNA or pathologic changes in the muscles of double-knockout mice, even when these mice were fed thymidine for 7 months. However, they found intense lesions in the brain on T2-weighted MRI, and axonal edema by electron microscopic study of the brain of double-knockout mice. Haraguchi et al. (2002) concluded that inhibition of TYMP activity causes elevation of pyrimidine levels in plasma and consequent axonal swelling. </p><p>Replication and repair of DNA require equilibrated pools of deoxynucleoside triphosphate precursors. Lopez et al. (2009) generated Tymp and Upp1 double-knockout mice, which showed severe Tymp deficiency, increased thymidine and deoxyuridine in tissues, and elevated mitochondrial deoxythymidine triphosphate. As consequences of the nucleotide pool imbalances, brains of mutant mice developed partial depletion of mtDNA, deficiencies of respiratory chain complexes, and encephalopathy. These findings largely account for the pathogenesis of MNGIE, the first inherited human disorder of nucleoside metabolism associated with somatic DNA instability. </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>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
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</span>
|
|
<strong>14 Selected Examples):</strong>
|
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</span>
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</h4>
|
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<div>
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<p />
|
|
</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)</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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|
|
|
TYMP, GLU289ALA
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|
<br />
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|
|
SNP: rs121913036,
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|
|
|
gnomAD: rs121913036,
|
|
|
|
|
|
ClinVar: RCV000018133, RCV000498727, RCV001276276
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In patients with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), Nishino et al. (1999) identified a 3371A-C transversion in exon 7 of the ECGF1 gene, resulting in a glu289-to-ala (E289A) substitution. This mutation was seen in homozygosity in an Ashkenazi Jewish patient and in compound heterozygosity in 4 other patients of German American (131222.0002), German (131222.0006), English (131222.0008), and European American ancestry. The mutation was associated with mitochondrial deletions in skeletal muscle, presumably resulting from mtDNA depletion. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TYMP, IVS4DS, 1504T-C
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs797044454,
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|
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|
|
|
|
|
ClinVar: RCV000018134
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), Nishino et al. (1999) identified compound heterozygosity for 2 mutations in the TYMP gene: E289A (131222.0001), and a 1504T-C transition in intron 4 that altered the splice donor site. When assayed by RT-PCR in leukocytes, the latter mutation caused skipping of exon 4. This would lead to loss of 33 amino acids in the mature protein and deletion of the thymidine phosphorylase consensus. The mutations were associated with mitochondrial deletions in skeletal muscle, presumably resulting from mtDNA depletion. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TYMP, GLY145ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121913037,
|
|
|
|
|
|
gnomAD: rs121913037,
|
|
|
|
|
|
ClinVar: RCV000018135, RCV001049989, RCV001276278
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In patients with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), Nishino et al. (1999) identified a 1419A-C transversion in exon 4 of the ECGF1 gene, causing a gly145-to-arg (G145R) substitution. The mutation was found in homozygosity in 2 Puerto Rican and 1 Israeli patient. The mutation, in the region of the thymidine phosphorylase consensus, was associated with multiple mtDNA deletions in skeletal muscle, presumably resulting from mtDNA depletion. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TYMP, LYS222ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs149977726,
|
|
|
|
|
|
gnomAD: rs149977726,
|
|
|
|
|
|
ClinVar: RCV000018136, RCV000497545, RCV001831582
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Nishino et al. (2000) reported an African American patient with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), who was compound heterozygous for 2 mutations in the TYMP gene: a 2744A-G transition, resulting in a lys222-to-arg (L222R) substitution, and a 1-bp insertion (4196insC; 131222.0005). This patient had previously been described by Nishino et al. (1999), who found that the missense mutation disrupted the thymidine phosphorylase phosphate binding site and that the mutations were associated with multiple mtDNA deletions in skeletal muscle, presumably resulting from mtDNA depletion. (Nishino et al. (1999) erroneously stated that the missense mutation in this patient, who was described as Jamaican, was a lys222-to-ser (K222S) substitution.) </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TYMP, 1-BP INS, 4196C
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs786205097,
|
|
|
|
|
|
|
|
ClinVar: RCV000018137
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 1-bp insertion in the TYMP gene (4196insC) that was found in compound heterozygous state in a patient with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), by Nishino et al. (2000) and Nishino et al. (1999), see 131222.0004. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TYMP, IVS8AS, 3867G-C
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs797044455,
|
|
|
|
|
|
gnomAD: rs797044455,
|
|
|
|
|
|
ClinVar: RCV000018138
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), Nishino et al. (1999) identified compound heterozygosity for 2 mutations in the TYMP gene: E289A (131222.0001), and a 3867G-C transversion that disrupted the splice acceptor site of intron 8, leading to skipping of exon 9 and disruption of the leucine zipper motif. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TYMP, 6-BP DEL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs786205098,
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|
|
|
|
|
gnomAD: rs786205098,
|
|
|
|
|
|
ClinVar: RCV000018139
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), Nishino et al. (1999) identified a homozygous 6-bp deletion in exon 9 of the ECGF1 gene that resulted in loss of leucine-397 and alanine-398. Although neither amino acid is strictly conserved, the authors suggested that their loss could alter the structure and enzymatic activity of the thymidine phosphorylase protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
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|
|
</div>
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|
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|
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<div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
TYMP, GLY153SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121913038,
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|
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|
|
|
gnomAD: rs121913038,
|
|
|
|
|
|
ClinVar: RCV000018140, RCV001052862, RCV001826476
|
|
|
|
|
|
</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 patients with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), Nishino et al. (1999) identified a 1443G-A transition in the ECGF1 gene, resulting in a gly153-to-ser (G153S) substitution. The mutation was identified in homozygosity in an English patient and in compound heterozygosity with the E289A mutation (131222.0001) in another English and 1 European American patient. </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>.0009 MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)</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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TYMP, ARG44GLN
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<br />
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SNP: rs28931613,
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ClinVar: RCV000018141, RCV002513094
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 Spanish sisters with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), Gamez et al. (2002) identified a homozygous 435G-A transition in the ECGF1 gene, resulting in an arg44-to-gln (R44Q) substitution in the mature protein. The authors noted that arg44 is located in the N-terminal domain of the protein and that the substitution of a positively charged (arg) by an uncharged (gln) amino acid could account for loss of enzyme activity in the 2 affected sisters. The mother and an unaffected sister were heterozygous for the mutation. Clinically, the affected sisters presented with variable phenotypes: one had predominantly gastrointestinal symptoms and the other had ophthalmoparesis. </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>.0010 MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)</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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TYMP, IVS1AS, G-C, -1
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<br />
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SNP: rs767245071,
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gnomAD: rs767245071,
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ClinVar: RCV000018142, RCV000599020, RCV001276279
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a patient with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as classic mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) but without skeletal muscle involvement at the morphologic, enzymatic, or mtDNA level, Szigeti et al. (2004) identified a homozygous G-to-C transversion at the splice acceptor site of exon 2 of the ECGF1 gene. The mutation resulted in skipping of exon 2 and loss of function of the protein, which was confirmed by the markedly reduced enzyme activity measured in peripheral blood. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0011 MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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TYMP, VAL208MET
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<br />
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SNP: rs121913039,
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|
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|
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gnomAD: rs121913039,
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|
|
ClinVar: RCV000018143, RCV000199543
|
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|
|
</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated women with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as late-onset mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), Marti et al. (2005) identified compound heterozygosity for 2 mutations in the ECGF1 gene. Both patients had a 2398G-A transition, resulting in a val208-to-met (V208M) substitution. In addition, 1 patient had a 3535G-C transversion, resulting in a gly311-to-arg substitution (G311R; 131222.0012), and the other had a 2381G-C transversion, resulting in an arg202-to-thr substitution (R202T; 131222.0013). The patients had onset of gastrointestinal symptoms at age 42 and 40 years, respectively. Biochemical analysis showed 15 to 16% residual enzyme activity in both patients, which likely accounted for the later onset. </p>
|
|
</span>
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|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
|
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TYMP, GLY311ARG
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<br />
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|
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SNP: rs121913040,
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|
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gnomAD: rs121913040,
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|
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|
|
|
ClinVar: RCV000018144
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the gly311-to-arg (G311R) mutation in the TYMP gene that was found in compound heterozygous state in patients with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as late-onset mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), by Marti et al. (2005), see 131222.0011. </p>
|
|
</span>
|
|
</div>
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|
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
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<span class="mim-text-font">
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TYMP, ARG202THR
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|
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<br />
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|
|
SNP: rs121913041,
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|
|
|
|
|
gnomAD: rs121913041,
|
|
|
|
|
|
ClinVar: RCV000018145, RCV003228895
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the arg202-to-thr (R202T) mutation in the TYMP gene that was found in compound heterozygous state in patients with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041), manifest as late-onset mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), by Marti et al. (2005), see 131222.0011. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 MITOCHONDRIAL DNA DEPLETION SYNDROME 1 (MNGIE TYPE)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
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|
|
|
TYMP, LEU285PRO
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs121913042,
|
|
|
|
|
|
gnomAD: rs121913042,
|
|
|
|
|
|
ClinVar: RCV000018146, RCV003330395, RCV003556042
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an African American man with mitochondrial DNA depletion syndrome-1 (MTDPS1; 603041) manifest as late-onset mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), Marti et al. (2005) identified compound heterozygosity for 2 mutations in the ECGF1 gene: a 3359T-C transition, resulting in a leu285-to-pro (L285P) substitution, and a G153S mutation (131222.0008). The patient had onset of lower gastrointestinal bleeding at age 52 years, followed by peripheral neuropathy, external ophthalmoplegia, and leukoencephalopathy. Biochemical analysis showed 9 to 13% residual enzyme activity, which likely accounted for the later onset. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
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|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
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<div>
|
|
<ol>
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<li>
|
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<p class="mim-text-font">
|
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Asai, K., Nakanishi, K., Isobe, I., Eksioglu, Y. Z., Hirano, A., Hama, K., Miyamoto, T., Kato, T.
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<strong>Neurotrophic action of gliostatin on cortical neurons: identity of gliostatin and platelet-derived endothelial cell growth factor.</strong>
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J. Biol. Chem. 267: 20311-20316, 1992.
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[PubMed: 1400349]
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<p class="mim-text-font">
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Gamez, J., Ferreiro, C., Accarino, M. L., Guarner, L., Tadesse, S., Marti, R. A., Andreu, A. L., Raguer, N., Cervera, C., Hirano, M.
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<strong>Phenotypic variability in a Spanish family with MNGIE.</strong>
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Neurology 59: 455-457, 2002.
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Griffiths, L., Stratford, I. J.
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<strong>Platelet-derived endothelial cell growth factor thymidine phosphorylase in tumour growth and response to therapy.</strong>
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Brit. J. Cancer 76: 689-693, 1997.
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Hagiwara, K., Stenman, G., Honda, H., Sahlin, P., Andersson, A., Miyazono, K., Heldin, C. H., Ishikawa, F., Takaku, F.
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<strong>Organization and chromosomal localization of the human platelet-derived endothelial cell growth factor gene.</strong>
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Molec. Cell. Biol. 11: 2125-2132, 1991.
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[PubMed: 2005900]
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Haraguchi, M., Tsujimoto, H., Fukushima, M., Higuchi, I., Kuribayashi, H., Utsumi, H., Nakayama, A., Hashizume, Y., Hirato, J., Yoshida, H., Hara, H., Hamano, S., and 17 others.
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<strong>Targeted deletion of both thymidine phosphorylase and uridine phosphorylase and consequent disorders in mice.</strong>
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Molec. Cell. Biol. 22: 5212-5221, 2002.
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[PubMed: 12077348]
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[Full Text: https://doi.org/10.1128/MCB.22.14.5212-5221.2002]
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Hirano, M., Lagier-Tourenne, C., Valentino, M. L., Marti, R., Nishigaki, Y.
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<strong>Thymidine phosphorylase mutations cause instability of mitochondrial DNA.</strong>
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Gene 354: 152-156, 2005.
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[PubMed: 15975738]
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[Full Text: https://doi.org/10.1016/j.gene.2005.04.041]
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<p class="mim-text-font">
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Ishikawa, F., Miyazono, K., Hellman, U., Drexler, H., Wernstedt, C., Hagiwara, K., Usuki, K., Takaku, F., Risau, W., Heldin, C.-H.
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<strong>Identification of angiogenic activity and the cloning and expression of platelet-derived endothelial cell growth factor.</strong>
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Nature 338: 557-562, 1989.
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[PubMed: 2467210]
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[Full Text: https://doi.org/10.1038/338557a0]
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<p class="mim-text-font">
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Lopez, L. C., Akman, H. O., Garcia-Cazorla, A., Dorado, B., Marti, R., Nishino, I., Tadesse, S., Pizzorno, G., Shungu, D., Bonilla, E., Tanji, K., Hirano, M.
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<strong>Unbalanced deoxynucleotide pools cause mitochondrial DNA instability in thymidine phosphorylase-deficient mice.</strong>
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Hum. Molec. Genet. 18: 714-722, 2009.
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[PubMed: 19028666]
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[Full Text: https://doi.org/10.1093/hmg/ddn401]
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</p>
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<li>
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<p class="mim-text-font">
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Marti, R., Verschuuren, J. J. G. M., Buchman, A., Hirano, I., Tadesse, S., van Kuilenburg, A. B. P., van Gennip, A. H., Poorthuis, B. J. H. M., Hirano, M.
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<strong>Late-onset MNGIE due to partial loss of thymidine phosphorylase activity.</strong>
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Ann. Neurol. 58: 649-652, 2005.
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[PubMed: 16178026]
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[Full Text: https://doi.org/10.1002/ana.20615]
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</p>
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<p class="mim-text-font">
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Matsukawa, K., Moriyama, A., Kawai, Y., Asai, K., Kato, T.
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<strong>Tissue distribution of human gliostatin/platelet-derived endothelial cell growth factor (PD-ECGF) and its drug-induced expression.</strong>
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Biochim. Biophys. Acta 1314: 71-82, 1996.
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[PubMed: 8972720]
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[Full Text: https://doi.org/10.1016/s0167-4889(96)00078-x]
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</p>
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<p class="mim-text-font">
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Nishino, I., Spinazzola, A., Hirano, M.
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<strong>Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder.</strong>
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Science 283: 689-692, 1999.
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[PubMed: 9924029]
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[Full Text: https://doi.org/10.1126/science.283.5402.689]
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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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|
Nishino, I., Spinazzola, A., Papadimitriou, A., Hammans, S., Steiner, I., Hahn, C. D., Connolly, A. M., Verloes, A., Guimaraes, J., Maillard, I., Hamano, H., Donati, M. A., and 13 others.
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<strong>Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations.</strong>
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Ann. Neurol. 47: 792-800, 2000.
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[PubMed: 10852545]
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</p>
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<li>
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<p class="mim-text-font">
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Stenman, G., Sahlin, P., Dumanski, J. P., Hagiwara, K., Ishikawa, F., Miyazono, K., Collins, V. P., Heldin, C.-H.
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<strong>Regional localization of the human platelet-derived endothelial cell growth factor (ECGF1) gene to chromosome 22q13.</strong>
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Cytogenet. Cell Genet. 59: 22-23, 1992.
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[PubMed: 1733667]
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[Full Text: https://doi.org/10.1159/000133191]
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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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|
Stenman, G., Sahlin, P., Hagiwara, K., Dumanski, J., Collins, V., Heldin, C.-H.
|
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<strong>Mapping of the human platelet-derived endothelial cell growth factor (PD-ECGF) gene to chromosome 22q13. (Abstract)</strong>
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|
Cytogenet. Cell Genet. 58: 2051 only, 1991.
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|
</p>
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</li>
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<li>
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|
<p class="mim-text-font">
|
|
Suomalainen, A., Isohanni, P.
|
|
<strong>Mitochondrial DNA depletion syndromes: many genes, common mechanisms.</strong>
|
|
Neuromusc. Disord. 20: 429-437, 2010.
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[PubMed: 20444604]
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[Full Text: https://doi.org/10.1016/j.nmd.2010.03.017]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Szigeti, K., Wong, L.-J. C., Perng, C.-L., Saifi, G. M., Eldin, K., Adesina, A. M., Cass, D. L., Hirano, M., Lupski, J. R., Scaglia, F.
|
|
<strong>MNGIE with lack of skeletal muscle involvement and a novel TP splice site mutation.</strong>
|
|
J. Med. Genet. 41: 125-129, 2004.
|
|
|
|
|
|
[PubMed: 14757860]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1136/jmg.2003.013789]
|
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Usuki, K., Saras, J., Waltenberger, J., Miyazono, K., Pierce, G., Thomason, A., Heldin, C.-H.
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<strong>Platelet-derived endothelial cell growth factor has thymidine phosphorylase activity.</strong>
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Biochem. Biophys. Res. Commun. 184: 1311-1316, 1992.
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[PubMed: 1590793]
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[Full Text: https://doi.org/10.1016/s0006-291x(05)80025-7]
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Cassandra L. Kniffin - updated : 12/9/2010<br>George E. Tiller - updated : 8/10/2009<br>Patricia A. Hartz - updated : 8/30/2006<br>Cassandra L. Kniffin - updated : 12/1/2005<br>Marla J. F. O'Neill - updated : 9/20/2004<br>Victor A. McKusick - updated : 5/2/2003<br>Cassandra L. Kniffin - updated : 10/3/2002<br>Ada Hamosh - updated : 1/28/1999
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Victor A. McKusick : 8/6/1991
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