3855 lines
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3855 lines
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Entry
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- *188250 - THYMIDINE KINASE, MITOCHONDRIAL; TK2
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- OMIM
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<p>
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<span class="h4">*188250</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<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/188250">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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</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=ENSG00000166548;t=ENST00000544898" 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=7084" 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=188250" 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 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=ENSG00000166548;t=ENST00000544898" 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_001172643,NM_001172644,NM_001172645,NM_001271934,NM_001271935,NM_001272050,NM_004614,NR_073520" 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_004614" 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=188250" 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=01770&isoform_id=01770_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/TK2" 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/1905969,1905974,23304350,25167087,119603419,119603420,119603421,119603422,119603423,134152411,148745750,194378116,194381102,194381344,194383270,221045840,254763443,290656936,290656975,290657146,290657203,311347738,311347740,311347742,311347744,311347746,311347748,311347750,311347752,311347754,311347756,311347758,311347760,311347762,311347764,311347766,311347768,311347770,311347772,311347774,311347776,311347778,311347780,311347782,311347784,311347786,311347788,311347790,311347792,311347794,311347796,311347798,311347800,311347802,311347804,311347806,311347808,311347810,311347812,311347814,311347816,429836851,429836854,440309859,2129658336,2129658338,2129658340,2129658342,2129658344,2129658346" 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/O00142" 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=7084" 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=ENSG00000166548;t=ENST00000544898" 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=TK2" 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=TK2" 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+7084" 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/TK2" 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:7084" 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/7084" 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=chr16&hgg_gene=ENST00000544898.6&hgg_start=66508003&hgg_end=66550291&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/genes/HGNC:11831" 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/tk2" 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=188250[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=188250[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/ENSG00000166548" 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=TK2" 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=TK2" 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=TK2" 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=TK2&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/PA36535" 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:11831" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0022338.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1913266" 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/TK2#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:1913266" 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/7084/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=7084" 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-040718-243" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:7084" 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=TK2&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 703527003<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
|
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188250
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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 KINASE, MITOCHONDRIAL; TK2
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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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<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=TK2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TK2</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/16/511?start=-3&limit=10&highlight=511">16q21</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr16:66508003-66550291&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'})">16:66,508,003-66,550,291</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>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
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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>
|
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Location
|
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</th>
|
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<th>
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Phenotype
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=617069,609560" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
|
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</th>
|
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<th>
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|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
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Inheritance
|
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</th>
|
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<th>
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Phenotype <br /> mapping key
|
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</th>
|
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="2">
|
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<span class="mim-font">
|
|
<a href="/geneMap/16/511?start=-3&limit=10&highlight=511">
|
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16q21
|
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</a>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
?Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3
|
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<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
|
|
<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
|
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</span>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
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|
<a href="/entry/617069"> 617069 </a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Mitochondrial DNA depletion syndrome 2 (myopathic type)
|
|
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/609560"> 609560 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
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</td>
|
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<td>
|
|
<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>
|
|
</td>
|
|
</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
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<p>Thymidine kinase-2 (TK2) is a mitochondrial deoxyribonucleoside kinase that phosphorylates thymidine, deoxycytidine, and deoxyuridine, as well as antiviral and anticancer nucleoside analogs (<a href="#5" class="mim-tip-reference" title="Johansson, M., Karlsson, A. <strong>Cloning of the cDNA and chromosome localization of the gene for human thymidine kinase 2.</strong> J. Biol. Chem. 272: 8454-8458, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9079672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9079672</a>] [<a href="https://doi.org/10.1074/jbc.272.13.8454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9079672">Johansson and Karlsson, 1997</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9079672" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Johansson, M., Karlsson, A. <strong>Cloning of the cDNA and chromosome localization of the gene for human thymidine kinase 2.</strong> J. Biol. Chem. 272: 8454-8458, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9079672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9079672</a>] [<a href="https://doi.org/10.1074/jbc.272.13.8454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9079672">Johansson and Karlsson (1997)</a> cloned cDNAs encoding human TK2. The gene encodes a 234-amino acid polypeptide. Although TK2 is believed to reside in mitochondria, it contains no mitochondrial translocation signal sequence. Northern blot analysis revealed that TK2 was ubiquitously expressed as 2 transcripts of 2.4 and 4 kb. Expression of the TK2 cDNA resulted in a 60-kD protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9079672" 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>Based on the partial protein sequence of human TK2, <a href="#15" class="mim-tip-reference" title="Wang, L., Munch-Petersen, B., Herrstrom Sjoberg, A., Hellman, U., Bergman, T., Jornvall, H., Eriksson, S. <strong>Human thymidine kinase 2: molecular cloning and characterisation of the enzyme activity with antiviral and cytostatic nucleoside substrates.</strong> FEBS Lett. 443: 170-174, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9989599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9989599</a>] [<a href="https://doi.org/10.1016/s0014-5793(98)01711-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9989599">Wang et al. (1999)</a> isolated a human brain TK2 cDNA. <a href="#15" class="mim-tip-reference" title="Wang, L., Munch-Petersen, B., Herrstrom Sjoberg, A., Hellman, U., Bergman, T., Jornvall, H., Eriksson, S. <strong>Human thymidine kinase 2: molecular cloning and characterisation of the enzyme activity with antiviral and cytostatic nucleoside substrates.</strong> FEBS Lett. 443: 170-174, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9989599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9989599</a>] [<a href="https://doi.org/10.1016/s0014-5793(98)01711-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9989599">Wang et al. (1999)</a> noted that although the cDNA they isolated corresponds to the full-length mature protein, it is likely to be incomplete because it lacks the coding region for a mitochondrial target presequence. They reported that the predicted protein sequence matched that of purified TK2, but differed at the N terminus and at amino acid 28 from the TK2 sequence deduced by <a href="#5" class="mim-tip-reference" title="Johansson, M., Karlsson, A. <strong>Cloning of the cDNA and chromosome localization of the gene for human thymidine kinase 2.</strong> J. Biol. Chem. 272: 8454-8458, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9079672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9079672</a>] [<a href="https://doi.org/10.1074/jbc.272.13.8454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9079672">Johansson and Karlsson (1997)</a>. TK2 shares approximately 40% identity with deoxycytidine kinase (<a href="/entry/125450">125450</a>) and deoxyguanosine kinase (DGUOK; <a href="/entry/601465">601465</a>) on the amino acid level. Northern blot analysis indicated that the TK2 gene was expressed as multiple transcripts, some of which show a tissue-specific pattern. The highest levels of expression were observed in testis and ovary. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9079672+9989599" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By screening a human genomic BAC library with the TK2 cDNA reported by <a href="#15" class="mim-tip-reference" title="Wang, L., Munch-Petersen, B., Herrstrom Sjoberg, A., Hellman, U., Bergman, T., Jornvall, H., Eriksson, S. <strong>Human thymidine kinase 2: molecular cloning and characterisation of the enzyme activity with antiviral and cytostatic nucleoside substrates.</strong> FEBS Lett. 443: 170-174, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9989599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9989599</a>] [<a href="https://doi.org/10.1016/s0014-5793(98)01711-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9989599">Wang et al. (1999)</a>, followed by database analysis, <a href="#16" class="mim-tip-reference" title="Wang, L., Saada, A., Eriksson, S. <strong>Kinetic properties of mutant human thymidine kinase 2 suggest a mechanism for mitochondrial DNA depletion myopathy.</strong> J. Biol. Chem. 278: 6963-6968, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12493767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12493767</a>] [<a href="https://doi.org/10.1074/jbc.M206143200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12493767">Wang et al. (2003)</a> obtained a full-length TK2 cDNA. The deduced protein contains 265 amino acids and has an N-terminal mitochondrial leader sequence. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12493767+9989599" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Sato, N., Amino, T., Kobayashi, K., Asakawa, S., Ishiguro, T., Tsunemi, T., Takahashi, M., Matsuura, T., Flanigan, K. M., Iwasaki, S., Ishino, F., Saito, Y., and 9 others. <strong>Spinocerebellar ataxia type 31 is associated with 'inserted' penta-nucleotide repeats containing (TGGAA)n.</strong> Am. J. Hum. Genet. 85: 544-557, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19878914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19878914</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19878914[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/10.1016/j.ajhg.2009.09.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19878914">Sato et al. (2009)</a> identified a number of TK2 splice variants that initiated in exons 8 or 9 and included further upstream exons. RT-PCR detected variable expression of TK2 upstream exons in a wide variety of tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19878914" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Gross, M. B. <strong>Personal Communication.</strong> Baltimore, Md. 11/3/2009."None>Gross (2009)</a> noted that a revised sequence for TK2 (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NP_004605.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NP_004605.3</a>) indicates that the full-length TK2 protein contains 307 amino acids. <a href="#3" class="mim-tip-reference" title="Behin, A., Jardel, C., Claeys, K. G., Fagart, J., Louha, M., Romero, N. B., Laforet, P., Eymard, B., Lombes, A. <strong>Adult cases of mitochondrial DNA depletion due to TK2 defect: an expanding spectrum.</strong> Neurology 78: 644-648, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22345218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22345218</a>] [<a href="https://doi.org/10.1212/WNL.0b013e318248df2b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22345218">Behin et al. (2012)</a> noted that the TK2 sequence had been revised again (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NP_004605.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NP_004605.4</a>) and that the full-length 265-amino acid TK2 protein lacks 42 N-terminal amino acids found in the earlier sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NP_004605.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NP_004605.3</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22345218" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Johansson, M., Karlsson, A. <strong>Cloning of the cDNA and chromosome localization of the gene for human thymidine kinase 2.</strong> J. Biol. Chem. 272: 8454-8458, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9079672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9079672</a>] [<a href="https://doi.org/10.1074/jbc.272.13.8454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9079672">Johansson and Karlsson (1997)</a> found that expression of the TK2 cDNA resulted in a protein with phosphorylation activity similar to purified human TK2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9079672" 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="#15" class="mim-tip-reference" title="Wang, L., Munch-Petersen, B., Herrstrom Sjoberg, A., Hellman, U., Bergman, T., Jornvall, H., Eriksson, S. <strong>Human thymidine kinase 2: molecular cloning and characterisation of the enzyme activity with antiviral and cytostatic nucleoside substrates.</strong> FEBS Lett. 443: 170-174, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9989599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9989599</a>] [<a href="https://doi.org/10.1016/s0014-5793(98)01711-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9989599">Wang et al. (1999)</a> characterized both recombinant and native TK2 forms and found that the enzyme has broad substrate specificity and complex kinetics, suggesting that it may play a role in the activation of chemotherapeutic nucleoside analogs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9989599" 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="#11" class="mim-tip-reference" title="Saada, A., Shaag, A., Mandel, H., Nevo, Y., Eriksson, S., Elpeleg, O. <strong>Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy.</strong> Nature Genet. 29: 342-344, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11687801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11687801</a>] [<a href="https://doi.org/10.1038/ng751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11687801">Saada et al. (2001)</a> stated that the TK2 gene contains 10 exons. <a href="#12" class="mim-tip-reference" title="Sato, N., Amino, T., Kobayashi, K., Asakawa, S., Ishiguro, T., Tsunemi, T., Takahashi, M., Matsuura, T., Flanigan, K. M., Iwasaki, S., Ishino, F., Saito, Y., and 9 others. <strong>Spinocerebellar ataxia type 31 is associated with 'inserted' penta-nucleotide repeats containing (TGGAA)n.</strong> Am. J. Hum. Genet. 85: 544-557, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19878914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19878914</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19878914[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/10.1016/j.ajhg.2009.09.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19878914">Sato et al. (2009)</a> determined that the TK2 gene contains 16 exons, which are subject to extensive alternative splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11687801+19878914" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The gene for mitochondrial TK2 is on chromosome 16 (<a href="#17" class="mim-tip-reference" title="Willecke, K., Reber, T., Kucherlapati, R. S., Ruddle, F. H. <strong>Human mitochondrial thymidine kinase is coded for by a gene on chromosome 16 of the nucleus.</strong> Somat. Cell Genet. 3: 237-245, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/605384/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">605384</a>] [<a href="https://doi.org/10.1007/BF01538743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="605384">Willecke et al., 1977</a>). <a href="#5" class="mim-tip-reference" title="Johansson, M., Karlsson, A. <strong>Cloning of the cDNA and chromosome localization of the gene for human thymidine kinase 2.</strong> J. Biol. Chem. 272: 8454-8458, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9079672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9079672</a>] [<a href="https://doi.org/10.1074/jbc.272.13.8454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9079672">Johansson and Karlsson (1997)</a> found 2 STS markers in the TK2 cDNA that map to chromosome 16q22. The TK2 gene partially overlaps the BEAN gene (<a href="/entry/612051">612051</a>) on chromosome 16q22.1 and is transcribed in the opposite orientation (<a href="#12" class="mim-tip-reference" title="Sato, N., Amino, T., Kobayashi, K., Asakawa, S., Ishiguro, T., Tsunemi, T., Takahashi, M., Matsuura, T., Flanigan, K. M., Iwasaki, S., Ishino, F., Saito, Y., and 9 others. <strong>Spinocerebellar ataxia type 31 is associated with 'inserted' penta-nucleotide repeats containing (TGGAA)n.</strong> Am. J. Hum. Genet. 85: 544-557, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19878914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19878914</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19878914[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/10.1016/j.ajhg.2009.09.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19878914">Sato et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=605384+19878914+9079672" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Autosomal Recessive Mitochondrial DNA Depletion Syndrome 2</em></strong></p><p>
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In 4 individuals with autosomal recessive mitochondrial DNA depletion syndrome-2 (MTDPS2; <a href="/entry/609560">609560</a>), manifest as onset in infancy of severe myopathy, <a href="#11" class="mim-tip-reference" title="Saada, A., Shaag, A., Mandel, H., Nevo, Y., Eriksson, S., Elpeleg, O. <strong>Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy.</strong> Nature Genet. 29: 342-344, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11687801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11687801</a>] [<a href="https://doi.org/10.1038/ng751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11687801">Saada et al. (2001)</a> identified 2 mutations in the TK2 gene (<a href="#0001">188250.0001</a>-<a href="#0002">188250.0002</a>). In these individuals, the activity of TK2 in muscle mitochondria was reduced to 14 to 45% of the mean value in healthy control individuals. <a href="#9" class="mim-tip-reference" title="Mandel, H., Szargel, R., Labay, V., Elpeleg, O., Saada, A., Shalata, A., Anbinder, Y., Berkowitz, D., Hartman, C., Barak, M., Eriksson, S., Cohen, N. <strong>The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA.</strong> Nature Genet. 29: 337-341, 2001. Note: Erratum: Nature Genet. 29: 491 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11687800/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11687800</a>] [<a href="https://doi.org/10.1038/ng746" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11687800">Mandel et al. (2001)</a> identified mutations in the DGUOK gene in another form of mtDNA depletion syndrome, the hepatocerebral form (MTDPS3; <a href="/entry/251880">251880</a>). They noted that the main supply of deoxynucleoside triphosphates (dNTPs) for mtDNA synthesis comes from the salvage pathway initiated by DGUOK and TK2. The association of mtDNA depletion with mutations in the genes encoding these 2 kinases suggested that the salvage pathway enzymes are involved in the maintenance of balanced mitochondrial dNTP pools. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11687800+11687801" 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="Behin, A., Jardel, C., Claeys, K. G., Fagart, J., Louha, M., Romero, N. B., Laforet, P., Eymard, B., Lombes, A. <strong>Adult cases of mitochondrial DNA depletion due to TK2 defect: an expanding spectrum.</strong> Neurology 78: 644-648, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22345218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22345218</a>] [<a href="https://doi.org/10.1212/WNL.0b013e318248df2b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22345218">Behin et al. (2012)</a> identified homozygous or compound heterozygous TK2 mutations (<a href="#0003">188250.0003</a>, <a href="#0005">188250.0005</a>, and <a href="#0006">188250.0006</a>) in 3 unrelated adult patients with a slowly progressive form of MTDPS2. All patients reported some form of hypotonia, early fatigue, or delayed walking in early childhood and 2 had proximal muscle weakness in childhood. Although muscle biopsies showed mtDNA depletion, there was higher residual mtDNA (about 30% of controls) compared to patients with a more severe form of the disorder (about 11% of controls). However, there were no apparent genotype/phenotype correlations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22345218" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Autosomal Recessive Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions 3</em></strong></p><p>
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By exome sequencing, <a href="#14" class="mim-tip-reference" title="Tyynismaa, H., Sun, R., Ahola-Erkkila, S., Almusa, H., Poyhonen, R., Korpela, M., Honkaniemi, J., Isohanni, P., Paetau, A., Wang, L., Suomalainen, A. <strong>Thymidine kinase 2 mutations in autosomal recessive progressive external ophthalmoplegia with multiple mitochondrial DNA deletions.</strong> Hum. Molec. Genet. 21: 66-75, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21937588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21937588</a>] [<a href="https://doi.org/10.1093/hmg/ddr438" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21937588">Tyynismaa et al. (2012)</a> identified compound heterozygous missense mutations in the TK2 gene (<a href="#0007">188250.0007</a> and <a href="#0008">188250.0008</a>) in 2 Finnish sisters with adult-onset autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOB3; <a href="/entry/617069">617069</a>). <a href="#14" class="mim-tip-reference" title="Tyynismaa, H., Sun, R., Ahola-Erkkila, S., Almusa, H., Poyhonen, R., Korpela, M., Honkaniemi, J., Isohanni, P., Paetau, A., Wang, L., Suomalainen, A. <strong>Thymidine kinase 2 mutations in autosomal recessive progressive external ophthalmoplegia with multiple mitochondrial DNA deletions.</strong> Hum. Molec. Genet. 21: 66-75, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21937588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21937588</a>] [<a href="https://doi.org/10.1093/hmg/ddr438" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21937588">Tyynismaa et al. (2012)</a> suggested that the higher residual activity of the mutants corresponded to the later onset and milder phenotypes in these patients compared to those with MTDPS2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21937588" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#1" class="mim-tip-reference" title="Akman, H. O., Dorado, B., Lopez, L. C., Garcia-Cazorla, A., Vila, M. R., Tanabe, L. M., Dauer, W. T., Bonilla, E., Tanji, K., Hirano, M. <strong>Thymidine kinase 2 (H126N) knockin mice show the essential role of balanced deoxynucleotide pools for mitochondrial DNA maintenance.</strong> Hum. Molec. Genet. 17: 2433-2440, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18467430/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18467430</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18467430[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/ddn143" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18467430">Akman et al. (2008)</a> created mice harboring a his126-to-asn (H126N) mutation in the Tk2 gene. The orthologous mutation in humans (H163N; see <a href="#0001">188250.0001</a>) causes an early muscle-specific form of mtDNA depletion syndrome. Homozygous mutant mice (Tk2 -/-) were obtained at the expected mendelian frequency and appeared normal at birth. However, at postnatal day 10, they showed several defects relative to wildtype and heterozygous mutant littermates, including growth retardation, reduced spontaneous activity, generalized coarse tremor, and impaired gait. They rapidly developed weakness, leading to severe stress or death by 2 weeks of age. Tk2 -/- animals showed reduced Tk2 activity in all tissues analyzed, with activity reduced to 1.7% of wildtype in brain, the most severely affected tissue. In Tk2 -/- mice, brain mitochondria had a dTTP concentration about 20% of wildtype, and liver mitochondria showed reduced levels of both dTTP and dCTP. The content of other dNTPs in these tissues was unchanged, and dNTP levels in other tissues were not affected. Depletion of mtDNA was most prominent in brain, where it was 12.5% of wildtype, and only brain showed decreased activities of respiratory chain enzymes, primarily complexes I and IV, and reduced ATP levels and ATP/ADP ratios. Spinal cord neurons had abnormal vacuolar changes, and the white matter of spinal cord and cortex showed evidence of activated glial cells. <a href="#1" class="mim-tip-reference" title="Akman, H. O., Dorado, B., Lopez, L. C., Garcia-Cazorla, A., Vila, M. R., Tanabe, L. M., Dauer, W. T., Bonilla, E., Tanji, K., Hirano, M. <strong>Thymidine kinase 2 (H126N) knockin mice show the essential role of balanced deoxynucleotide pools for mitochondrial DNA maintenance.</strong> Hum. Molec. Genet. 17: 2433-2440, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18467430/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18467430</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18467430[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/ddn143" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18467430">Akman et al. (2008)</a> concluded that, in contrast to the muscle-specific phenotype observed in patients with the H121N (now H163N) mutation, mice homozygous for the H126N mutation showed a rapidly progressive encephalomyelopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18467430" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Bartesaghi, S., Betts-Henderson, J., Cain, K., Dinsdale, D., Zhou, X., Karlsson, A., Salomoni, P., Nicotera, P. <strong>Loss of thymidine kinase 2 alters neuronal bioenergetics and leads to neurodegeneration.</strong> Hum. Molec. Genet. 19: 1669-1677, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20123860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20123860</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20123860[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/ddq043" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20123860">Bartesaghi et al. (2010)</a> demonstrated that in vivo loss of Tk2 activity in mice led to a severe ataxic phenotype, accompanied by reduced mtDNA copy number and decreased steady-state levels of electron transport chain proteins in the brain. In Tk2-deficient cerebellar neurons, these abnormalities were associated with impaired mitochondrial bioenergetic function, aberrant mitochondrial ultrastructure, and degeneration of selected neuronal types. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20123860" 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="Lopez-Gomez, C., Sanchez-Quintero, M. J., Lee, E. J., Kleiner, G., Tadesse, S., Xie, J., Akman, H. O., Gao, G., Hirano, M. <strong>Synergistic deoxynucleoside and gene therapies for thymidine kinase 2 deficiency.</strong> Ann. Neurol. 90: 640-652, 2021. Note: Erratum: Ann. Neurol. 91: 303 only, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34338329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34338329</a>] [<a href="https://doi.org/10.1002/ana.26185" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34338329">Lopez-Gomez et al. (2021)</a> evaluated the effects of AAV gene therapy with and without pyrimidine deoxynucleoside (deoxycytidine (dC) and thymidine (dT)) treatment in a mouse model of Tk2 deficiency. AAV9 delivery of TK2 cDNA (AAV9-TK2) to the mutant mice on postnatal day 1 rescued Tk2 activity in liver, brain, and muscle but not in kidneys. The treated mutant mice had delayed disease onset and longer lifespan compared to untreated mutant mice. When the mice were treated with sequential AAV dosing, a dose of AAV9-TK2 on postnatal day 1 and then a dose of AAV2-TK2 on day 29, vector induction was not increased in the kidneys and vector genomes per nucleus were decreased in the brain and muscle compared to the mice treated with only AAV9-TK2. However, survival of the AAV9-TK2/AAV2-TK2 treated mice was significantly increased compared to the AAV9-TK2 treated and untreated mutant mice. Growth curves, motor function, and strength were similar in the AAV9-TK2/AAV2-TK2 treated mice and the AAV9-TK2 treated mice, and neither treatment cohort developed head tremors. The mutant mice were also treated with sequential AAV9-TK2/AAV2-TK2 dosing and with oral dC and dT from postnatal day 21 and had improved growth, survival, and mtDNA copy number in liver and kidneys compared to the other treatment cohorts of mutant mice. <a href="#6" class="mim-tip-reference" title="Lopez-Gomez, C., Sanchez-Quintero, M. J., Lee, E. J., Kleiner, G., Tadesse, S., Xie, J., Akman, H. O., Gao, G., Hirano, M. <strong>Synergistic deoxynucleoside and gene therapies for thymidine kinase 2 deficiency.</strong> Ann. Neurol. 90: 640-652, 2021. Note: Erratum: Ann. Neurol. 91: 303 only, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34338329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34338329</a>] [<a href="https://doi.org/10.1002/ana.26185" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34338329">Lopez-Gomez et al. (2021)</a> concluded that dC and dT supplementation enhances the effects of TK2 gene therapy and supports the potential for future combination therapy in patients with TK2 deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34338329" 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=RCV000013545 OR RCV001386287 OR RCV004526595" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013545, RCV001386287, RCV004526595" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013545...</a>
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<p>Based on the revised protein sequence for TK2 (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NP_004605.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NP_004605.4</a>), the mutation designated HIS90ASN (H90N) and later HIS163ASN (H163N) is now referred to as HIS121ASN (H121N) (<a href="#3" class="mim-tip-reference" title="Behin, A., Jardel, C., Claeys, K. G., Fagart, J., Louha, M., Romero, N. B., Laforet, P., Eymard, B., Lombes, A. <strong>Adult cases of mitochondrial DNA depletion due to TK2 defect: an expanding spectrum.</strong> Neurology 78: 644-648, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22345218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22345218</a>] [<a href="https://doi.org/10.1212/WNL.0b013e318248df2b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22345218">Behin et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22345218" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an Ashkenazi Jewish patient with mitochondrial DNA depletion syndrome-2 (MTDPS2; <a href="/entry/609560">609560</a>), manifest as a myopathy, <a href="#11" class="mim-tip-reference" title="Saada, A., Shaag, A., Mandel, H., Nevo, Y., Eriksson, S., Elpeleg, O. <strong>Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy.</strong> Nature Genet. 29: 342-344, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11687801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11687801</a>] [<a href="https://doi.org/10.1038/ng751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11687801">Saada et al. (2001)</a> found a homozygous GC-to-AA substitution at nucleotides 267-268 of the TK2 gene, resulting in a his90-to-asn (HIS90ASN) substitution. The patient died at the age of 4 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11687801" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Wang, L., Saada, A., Eriksson, S. <strong>Kinetic properties of mutant human thymidine kinase 2 suggest a mechanism for mitochondrial DNA depletion myopathy.</strong> J. Biol. Chem. 278: 6963-6968, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12493767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12493767</a>] [<a href="https://doi.org/10.1074/jbc.M206143200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12493767">Wang et al. (2003)</a> found that recombinant human TK2 with the H121N mutation had a similar subunit structure compared with wildtype TK2. The H121N mutant enzyme had normal Km values for thymidine and deoxycytidine, but 2- and 3-fold lower Vmax values, respectively, compared with wildtype TK2 and markedly increased Km values for ATP, leading to decreased enzyme efficiency. Competition experiments revealed that thymidine and deoxycytidine interacted differently with the H121N mutant compared with wildtype TK2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12493767" 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>.0002 MITOCHONDRIAL DNA DEPLETION SYNDROME 2 (MYOPATHIC 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">rs137854430 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854430;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=rs137854430" 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=rs137854430" 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=RCV000013546 OR RCV003556012" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013546, RCV003556012" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013546...</a>
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<p>Based on the revised protein sequence for TK2 (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NP_004605.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NP_004605.4</a>), the mutation designated ILE181ASN (I181N) and later ILE254ASN (I254N) is now referred to as ILE212ASN (I212N) (<a href="#3" class="mim-tip-reference" title="Behin, A., Jardel, C., Claeys, K. G., Fagart, J., Louha, M., Romero, N. B., Laforet, P., Eymard, B., Lombes, A. <strong>Adult cases of mitochondrial DNA depletion due to TK2 defect: an expanding spectrum.</strong> Neurology 78: 644-648, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22345218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22345218</a>] [<a href="https://doi.org/10.1212/WNL.0b013e318248df2b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22345218">Behin et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22345218" 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 3 Muslim-Arab infants with mitochondrial DNA depletion syndrome-2 (MTDPS2; <a href="/entry/609560">609560</a>), manifest as a myopathy, <a href="#11" class="mim-tip-reference" title="Saada, A., Shaag, A., Mandel, H., Nevo, Y., Eriksson, S., Elpeleg, O. <strong>Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy.</strong> Nature Genet. 29: 342-344, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11687801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11687801</a>] [<a href="https://doi.org/10.1038/ng751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11687801">Saada et al. (2001)</a> found a T-to-A transversion at nucleotide 542 of the TK2 gene, resulting in an ile181-to-asn (ILE181ASN) substitution. Two of the patients were mechanically ventilated at age 3 years at the time of the report; a third had died at age 19 months. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11687801" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Wang, L., Saada, A., Eriksson, S. <strong>Kinetic properties of mutant human thymidine kinase 2 suggest a mechanism for mitochondrial DNA depletion myopathy.</strong> J. Biol. Chem. 278: 6963-6968, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12493767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12493767</a>] [<a href="https://doi.org/10.1074/jbc.M206143200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12493767">Wang et al. (2003)</a> found that recombinant human TK2 with the I212N mutation had a similar subunit structure compared with wildtype TK2. However, the I212N mutant enzyme showed less than 1% activity compared with wildtype TK2 with all deoxynucleosides. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12493767" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137854431 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854431;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/rs137854431?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=rs137854431" 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=rs137854431" 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=RCV000013547 OR RCV000199738 OR RCV003883499 OR RCV003993743 OR RCV004757106" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013547, RCV000199738, RCV003883499, RCV003993743, RCV004757106" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013547...</a>
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<p>Based on the revised protein sequence for TK2 (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NP_004605.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NP_004605.4</a>), the mutation designated THR77MET (T77M) and later THR150MET (T150M) is now referred to as THR108MET (T108M) (<a href="#3" class="mim-tip-reference" title="Behin, A., Jardel, C., Claeys, K. G., Fagart, J., Louha, M., Romero, N. B., Laforet, P., Eymard, B., Lombes, A. <strong>Adult cases of mitochondrial DNA depletion due to TK2 defect: an expanding spectrum.</strong> Neurology 78: 644-648, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22345218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22345218</a>] [<a href="https://doi.org/10.1212/WNL.0b013e318248df2b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22345218">Behin et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22345218" 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="#8" class="mim-tip-reference" title="Mancuso, M., Salviati, L., Sacconi, S., Otaegui, D., Camano, P., Marina, A., Bacman, S., Moraes, C. T., Carlo, J. R., Garcia, M., Garcia-Alvarez, M., Monzon, L., Naini, A. B., Hirano, M., Bonilla, E., Taratuto, A. L., DiMauro, S., Vu, T. H. <strong>Mitochondrial DNA depletion: mutations in thymidine kinase gene with myopathy and SMA.</strong> Neurology 59: 1197-1202, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12391347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12391347</a>] [<a href="https://doi.org/10.1212/01.wnl.0000028689.93049.9a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12391347">Mancuso et al. (2002)</a> described 2 sibs with mitochondrial DNA depletion syndrome-2 (MTDPS2; <a href="/entry/609560">609560</a>) who were compound heterozygous for the previously described H90N mutation (<a href="#0001">188250.0001</a>) and a novel thr77-to-met (THR77MET) mutation. The proband was normal until 12 months of age when he developed frequent falls and progressive gait impairment, leading to inability to walk by age 26 months. By age 2 years he was unable to stand. He became dependent on mechanical ventilation by 3 years of age and died at 40 months of age. An older sister was similarly affected but with a more slowly evolving course. At age 16 months she began to have frequent falls, limb weakness, and gait abnormality, and by age 4 years she was no longer able to walk. She had elevated serum CK levels and lactic acidosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12391347" 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 family originally described by <a href="#13" class="mim-tip-reference" title="Tritschler, H.-J., Andreetta, F., Moraes, C. T., Bonilla, E., Arnaudo, E., Danon, M. J., Glass, S., Zelaya, B. M., Vamos, E., Telerman-Toppet, N., Shanske, S., Kadenbach, B., DiMauro, S., Schon, E. A. <strong>Mitochondrial myopathy of childhood associated with depletion of mitochondrial DNA.</strong> Neurology 42: 209-217, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1734306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1734306</a>] [<a href="https://doi.org/10.1212/wnl.42.1.209" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1734306">Tritschler et al. (1992)</a> in which 3 sibs had mitochondrial DNA depletion syndrome-2, <a href="#7" class="mim-tip-reference" title="Mancuso, M., Filosto, M., Bonilla, E., Hirano, M., Shanske, S., Vu, T. H., DiMauro, S. <strong>Mitochondrial myopathy of childhood associated with mitochondrial DNA depletion and a homozygous mutation (T77M) in the TK2 gene.</strong> Arch. Neurol. 60: 1007-1009, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12873860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12873860</a>] [<a href="https://doi.org/10.1001/archneur.60.7.1007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12873860">Mancuso et al. (2003)</a> identified homozygosity for the THR77MET mutation. The patients had 80 to 90% mitochondrial DNA depletion in muscle biopsy specimens, and all died of respiratory failure by age 40 months. The mutation is near the active site, in the alpha-4 helix of the protein, which is important for enzyme dimerization and nucleoside recognition. The authors noted that exon 5 is a hotspot for TK2 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12873860+1734306" 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="Behin, A., Jardel, C., Claeys, K. G., Fagart, J., Louha, M., Romero, N. B., Laforet, P., Eymard, B., Lombes, A. <strong>Adult cases of mitochondrial DNA depletion due to TK2 defect: an expanding spectrum.</strong> Neurology 78: 644-648, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22345218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22345218</a>] [<a href="https://doi.org/10.1212/WNL.0b013e318248df2b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22345218">Behin et al. (2012)</a> reported 2 unrelated patients who were homozygous for the T108M mutation but who had had a milder course and slower progression than previously associated with this mutation. One patient had hypotonia since birth, delayed early walking, and proximal muscle weakness in childhood, whereas the other showed early fatigue in childhood; both presented in their early thirties with more significant impairment. Features included waddling gait, distal and proximal muscle weakness, axial weakness, and respiratory insufficiency. One patient was wheelchair-bound and the other could not walk for more than 15 minutes. More variable features included ptosis, hypophonia, and facial weakness. Cognition, hearing, and cardiac function were normal. EMG showed a myogenic pattern, and muscle biopsies showed dystrophic changes consistent with a mitochondrial myopathy, including deficiencies of complexes I, III, and IV. Muscle mtDNA depletion was apparent, with mtDNA levels at about 30% of normal controls. This report expanded the phenotypic spectrum of MTDPS2 to include patients with much slower progression, which may have been due to better preservation of residual muscle mtDNA compared to more severely affected patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22345218" 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="Paradas, C., Gutierrez Rios, P., Rivas, E., Carbonell, P., Hirano, M., DiMauro, S. <strong>TK2 mutation presenting as indolent myopathy.</strong> Neurology 80: 504-506, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23303857/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23303857</a>] [<a href="https://doi.org/10.1212/WNL.0b013e31827f0ff7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23303857">Paradas et al. (2013)</a> reported a 22-year-old man, born of consanguineous parents, with MTDPS2 due to a homozygous T108M mutation. He had normal development until age 24 months, when he showed proximal muscle weakness of the lower limbs resulting in a waddling gait. At age 20, he had a nasal voice and mild proximal arm weakness. After sudden onset of respiratory arrest triggered by pneumonia, he had rapid worsening of the muscle weakness and became wheelchair-bound. He had severe axial and proximal muscle weakness, facial weakness without ptosis, pectoral atrophy, scapular winging, and ankle contractures. He also had significant gynecomastia of unclear etiology. Laboratory studies showed increased serum creatine kinase and normal serum lactate. Muscle samples showed dystrophic features, endomysial fibrosis, abnormally shaped mitochondria, decreased mitochondrial complex I activity (35% of normal), and multiple mtDNA deletions (45% residual mtDNA). Family history revealed a 3-year-old sister who died of respiratory failure due to muscular dystrophy as well as 2 infant deaths in previous generations. The report was notable for significant intrafamilial phenotypic heterogeneity. Functional studies of the T108M variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23303857" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 MITOCHONDRIAL DNA DEPLETION SYNDROME 2 (MYOPATHIC 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">rs137854432 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854432;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=rs137854432" 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=rs137854432" 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=RCV000013548" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013548" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013548</a>
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<p>Based on the revised protein sequence for TK2 (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NP_004605.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NP_004605.4</a>), the mutation designated ILE22MET (I22M) and later ILE95MET (I95M) is now referred to as ILE53MET (I53M) (<a href="#3" class="mim-tip-reference" title="Behin, A., Jardel, C., Claeys, K. G., Fagart, J., Louha, M., Romero, N. B., Laforet, P., Eymard, B., Lombes, A. <strong>Adult cases of mitochondrial DNA depletion due to TK2 defect: an expanding spectrum.</strong> Neurology 78: 644-648, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22345218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22345218</a>] [<a href="https://doi.org/10.1212/WNL.0b013e318248df2b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22345218">Behin et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22345218" 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 Hispanic family with nonconsanguineous parents, <a href="#8" class="mim-tip-reference" title="Mancuso, M., Salviati, L., Sacconi, S., Otaegui, D., Camano, P., Marina, A., Bacman, S., Moraes, C. T., Carlo, J. R., Garcia, M., Garcia-Alvarez, M., Monzon, L., Naini, A. B., Hirano, M., Bonilla, E., Taratuto, A. L., DiMauro, S., Vu, T. H. <strong>Mitochondrial DNA depletion: mutations in thymidine kinase gene with myopathy and SMA.</strong> Neurology 59: 1197-1202, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12391347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12391347</a>] [<a href="https://doi.org/10.1212/01.wnl.0000028689.93049.9a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12391347">Mancuso et al. (2002)</a> found that mitochondrial DNA depletion syndrome-2 (MTDPS2; <a href="/entry/609560">609560</a>) is caused by homozygosity for an ile22-to-met (ILE22MET) mutation in the TK2 gene. A brother and sister were affected. The sister had severe weakness and hypotonia from the first months of life and died at the age of 2 years. Her brother was normal until the age of 15 months, when he developed increasing lumbar lordosis and waddling gait. Arm and cervical muscles were involved later. By the age of 2 years he had lost his ability to walk. At the age of 3 years, he had severe proximal limb weakness, muscle wasting, areflexia, and scoliosis. Results of nerve conduction studies were normal, but EMG showed chronic partial denervation, with fibrillations and severe loss of motor unit potentials. These electrophysiologic findings were compatible with spinal muscular atrophy. At the time of the study, he was still alive at age 4 years. The evidence of lower motor neuron disease was taken to indicate that the clinical expression of TK2 mutations is not limited to myopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12391347" 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>.0005 MITOCHONDRIAL DNA DEPLETION SYNDROME 2 (MYOPATHIC 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> rs281865502 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs281865502;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/rs281865502?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=rs281865502" 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=rs281865502" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In an adult man with slowly progressive mitochondrial DNA depletion syndrome-2 (MTDPS2; <a href="/entry/609560">609560</a>), <a href="#3" class="mim-tip-reference" title="Behin, A., Jardel, C., Claeys, K. G., Fagart, J., Louha, M., Romero, N. B., Laforet, P., Eymard, B., Lombes, A. <strong>Adult cases of mitochondrial DNA depletion due to TK2 defect: an expanding spectrum.</strong> Neurology 78: 644-648, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22345218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22345218</a>] [<a href="https://doi.org/10.1212/WNL.0b013e318248df2b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22345218">Behin et al. (2012)</a> identified compound heterozygosity for 2 mutations in the TK2 gene: an 8-bp duplication in exon 1, resulting in a frameshift and premature termination (Trp4ValfsTer40), and a 268C-T transition in exon 4, resulting in an arg90-to-cys (R90C; <a href="#0006">188250.0006</a>) substitution in a region important for TK2 dimer stabilization. Each unaffected parent was heterozygous for 1 of the mutations. TK2 activity in patient fibroblasts was 4% of controls. The patient had mild ptosis at age 13 years, dysarthria at age 15, and proximal lower limb weakness at age 25. At age 31, he presented with ptosis, upper gaze limitation, hypophonia, axial and limb muscle weakness, and respiratory insufficiency, although he remained ambulatory. Laboratory investigations showed mild increased serum creatine kinase, and skeletal muscle biopsy showed mitochondrial defects with mtDNA depletion (about 30% residual mtDNA compared to controls). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22345218" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 MITOCHONDRIAL DNA DEPLETION SYNDROME 2 (MYOPATHIC 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> rs281865489 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs281865489;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/rs281865489?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=rs281865489" 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=rs281865489" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the arg90-to-cys (R90C) mutation in the TK2 gene that was found in compound heterozygous state in a patient with slowly progressive mitochondrial DNA depletion syndrome-2 (MTDPS2; <a href="/entry/609560">609560</a>) by <a href="#3" class="mim-tip-reference" title="Behin, A., Jardel, C., Claeys, K. G., Fagart, J., Louha, M., Romero, N. B., Laforet, P., Eymard, B., Lombes, A. <strong>Adult cases of mitochondrial DNA depletion due to TK2 defect: an expanding spectrum.</strong> Neurology 78: 644-648, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22345218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22345218</a>] [<a href="https://doi.org/10.1212/WNL.0b013e318248df2b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22345218">Behin et al. (2012)</a>, see <a href="#0005">188250.0005</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22345218" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE 3 (1 family)</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> rs137886900 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137886900;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/rs137886900?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=rs137886900" 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=rs137886900" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 Finnish sisters with adult-onset autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOB3; <a href="/entry/617069">617069</a>), <a href="#14" class="mim-tip-reference" title="Tyynismaa, H., Sun, R., Ahola-Erkkila, S., Almusa, H., Poyhonen, R., Korpela, M., Honkaniemi, J., Isohanni, P., Paetau, A., Wang, L., Suomalainen, A. <strong>Thymidine kinase 2 mutations in autosomal recessive progressive external ophthalmoplegia with multiple mitochondrial DNA deletions.</strong> Hum. Molec. Genet. 21: 66-75, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21937588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21937588</a>] [<a href="https://doi.org/10.1093/hmg/ddr438" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21937588">Tyynismaa et al. (2012)</a> identified compound heterozygous mutations in the TK2 gene: a c.673C-T transition, resulting in an arg225-to-trp (R225W) substitution, and a c.688A-G transition, resulting in a thr230-to-ala (T230A; <a href="#0008">188250.0008</a>) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were filtered against the dbSNP (build 130) and 1000 Genomes Project databases. The R225W mutation was not found in 400 Finnish control chromosomes, but the T230A mutation was found in 1 of 400 Finnish control chromosomes. Parental DNA was not available for segregation analysis. The mutated residues, while located within a highly conserved sequence block, are not themselves fully conserved, even among vertebrates. In vitro functional expression studies in E. coli showed that both mutant enzymes had higher Km and lower Vmax values compared to wildtype, resulting in decreased catalytic efficiencies (17-22% for T230A and 3-4% for R225W). Mitochondria isolated from both patients' cells showed TK2-specific activity between 22 and 54% of controls. <a href="#14" class="mim-tip-reference" title="Tyynismaa, H., Sun, R., Ahola-Erkkila, S., Almusa, H., Poyhonen, R., Korpela, M., Honkaniemi, J., Isohanni, P., Paetau, A., Wang, L., Suomalainen, A. <strong>Thymidine kinase 2 mutations in autosomal recessive progressive external ophthalmoplegia with multiple mitochondrial DNA deletions.</strong> Hum. Molec. Genet. 21: 66-75, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21937588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21937588</a>] [<a href="https://doi.org/10.1093/hmg/ddr438" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21937588">Tyynismaa et al. (2012)</a> suggested that the residual activity of the mutants corresponded to the later onset and milder phenotypes in these patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21937588" 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 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE 3 (1 family)</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> rs281865495 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs281865495;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/rs281865495?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=rs281865495" 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=rs281865495" 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=RCV000239458 OR RCV001852646" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000239458, RCV001852646" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000239458...</a>
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<p>For discussion of the thr230-to-ala (T230A) mutation in the TK2 gene that was found in compound heterozygous state in 2 sisters with adult-onset autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOB3; <a href="/entry/617069">617069</a>) by <a href="#14" class="mim-tip-reference" title="Tyynismaa, H., Sun, R., Ahola-Erkkila, S., Almusa, H., Poyhonen, R., Korpela, M., Honkaniemi, J., Isohanni, P., Paetau, A., Wang, L., Suomalainen, A. <strong>Thymidine kinase 2 mutations in autosomal recessive progressive external ophthalmoplegia with multiple mitochondrial DNA deletions.</strong> Hum. Molec. Genet. 21: 66-75, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21937588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21937588</a>] [<a href="https://doi.org/10.1093/hmg/ddr438" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21937588">Tyynismaa et al. (2012)</a>, see <a href="#0007">188250.0007</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21937588" 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>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
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<a id="Akman2008" class="mim-anchor"></a>
|
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Akman, H. O., Dorado, B., Lopez, L. C., Garcia-Cazorla, A., Vila, M. R., Tanabe, L. M., Dauer, W. T., Bonilla, E., Tanji, K., Hirano, M.
|
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<strong>Thymidine kinase 2 (H126N) knockin mice show the essential role of balanced deoxynucleotide pools for mitochondrial DNA maintenance.</strong>
|
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Hum. Molec. Genet. 17: 2433-2440, 2008.
|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18467430/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18467430</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18467430[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=18467430" 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/ddn143" target="_blank">Full Text</a>]
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|
|
Bartesaghi, S., Betts-Henderson, J., Cain, K., Dinsdale, D., Zhou, X., Karlsson, A., Salomoni, P., Nicotera, P.
|
|
<strong>Loss of thymidine kinase 2 alters neuronal bioenergetics and leads to neurodegeneration.</strong>
|
|
Hum. Molec. Genet. 19: 1669-1677, 2010.
|
|
|
|
|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20123860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20123860</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20123860[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=20123860" 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/ddq043" target="_blank">Full Text</a>]
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|
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|
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|
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|
|
Behin, A., Jardel, C., Claeys, K. G., Fagart, J., Louha, M., Romero, N. B., Laforet, P., Eymard, B., Lombes, A.
|
|
<strong>Adult cases of mitochondrial DNA depletion due to TK2 defect: an expanding spectrum.</strong>
|
|
Neurology 78: 644-648, 2012.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22345218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22345218</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22345218" 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/10.1212/WNL.0b013e318248df2b" target="_blank">Full Text</a>]
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</li>
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<li>
|
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<a id="4" class="mim-anchor"></a>
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<a id="Gross2009" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Gross, M. B.
|
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<strong>Personal Communication.</strong>
|
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Baltimore, Md. 11/3/2009.
|
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|
|
|
|
|
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</p>
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</div>
|
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</li>
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|
|
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|
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|
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Johansson, M., Karlsson, A.
|
|
<strong>Cloning of the cDNA and chromosome localization of the gene for human thymidine kinase 2.</strong>
|
|
J. Biol. Chem. 272: 8454-8458, 1997.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9079672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9079672</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9079672" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="6" class="mim-anchor"></a>
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|
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|
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Lopez-Gomez, C., Sanchez-Quintero, M. J., Lee, E. J., Kleiner, G., Tadesse, S., Xie, J., Akman, H. O., Gao, G., Hirano, M.
|
|
<strong>Synergistic deoxynucleoside and gene therapies for thymidine kinase 2 deficiency.</strong>
|
|
Ann. Neurol. 90: 640-652, 2021. Note: Erratum: Ann. Neurol. 91: 303 only, 2022.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34338329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34338329</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34338329" 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.26185" target="_blank">Full Text</a>]
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</li>
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<li>
|
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|
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<a id="Mancuso2003" class="mim-anchor"></a>
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|
|
<p class="mim-text-font">
|
|
Mancuso, M., Filosto, M., Bonilla, E., Hirano, M., Shanske, S., Vu, T. H., DiMauro, S.
|
|
<strong>Mitochondrial myopathy of childhood associated with mitochondrial DNA depletion and a homozygous mutation (T77M) in the TK2 gene.</strong>
|
|
Arch. Neurol. 60: 1007-1009, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12873860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12873860</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12873860" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1001/archneur.60.7.1007" target="_blank">Full Text</a>]
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|
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Mancuso, M., Salviati, L., Sacconi, S., Otaegui, D., Camano, P., Marina, A., Bacman, S., Moraes, C. T., Carlo, J. R., Garcia, M., Garcia-Alvarez, M., Monzon, L., Naini, A. B., Hirano, M., Bonilla, E., Taratuto, A. L., DiMauro, S., Vu, T. H.
|
|
<strong>Mitochondrial DNA depletion: mutations in thymidine kinase gene with myopathy and SMA.</strong>
|
|
Neurology 59: 1197-1202, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12391347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12391347</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12391347" 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/10.1212/01.wnl.0000028689.93049.9a" target="_blank">Full Text</a>]
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|
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<a id="9" class="mim-anchor"></a>
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<a id="Mandel2001" class="mim-anchor"></a>
|
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Mandel, H., Szargel, R., Labay, V., Elpeleg, O., Saada, A., Shalata, A., Anbinder, Y., Berkowitz, D., Hartman, C., Barak, M., Eriksson, S., Cohen, N.
|
|
<strong>The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA.</strong>
|
|
Nature Genet. 29: 337-341, 2001. Note: Erratum: Nature Genet. 29: 491 only, 2001.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11687800/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11687800</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11687800" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng746" target="_blank">Full Text</a>]
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<a id="10" class="mim-anchor"></a>
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<a id="Paradas2013" class="mim-anchor"></a>
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Paradas, C., Gutierrez Rios, P., Rivas, E., Carbonell, P., Hirano, M., DiMauro, S.
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<strong>TK2 mutation presenting as indolent myopathy.</strong>
|
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Neurology 80: 504-506, 2013.
|
|
|
|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23303857/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23303857</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23303857" 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/10.1212/WNL.0b013e31827f0ff7" target="_blank">Full Text</a>]
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<a id="11" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
|
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Saada, A., Shaag, A., Mandel, H., Nevo, Y., Eriksson, S., Elpeleg, O.
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<strong>Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy.</strong>
|
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Nature Genet. 29: 342-344, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11687801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11687801</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11687801" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng751" target="_blank">Full Text</a>]
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</p>
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<a id="12" class="mim-anchor"></a>
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<a id="Sato2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sato, N., Amino, T., Kobayashi, K., Asakawa, S., Ishiguro, T., Tsunemi, T., Takahashi, M., Matsuura, T., Flanigan, K. M., Iwasaki, S., Ishino, F., Saito, Y., and 9 others.
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<strong>Spinocerebellar ataxia type 31 is associated with 'inserted' penta-nucleotide repeats containing (TGGAA)n.</strong>
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Am. J. Hum. Genet. 85: 544-557, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19878914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19878914</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19878914[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=19878914" 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.ajhg.2009.09.019" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="Tritschler1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tritschler, H.-J., Andreetta, F., Moraes, C. T., Bonilla, E., Arnaudo, E., Danon, M. J., Glass, S., Zelaya, B. M., Vamos, E., Telerman-Toppet, N., Shanske, S., Kadenbach, B., DiMauro, S., Schon, E. A.
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<strong>Mitochondrial myopathy of childhood associated with depletion of mitochondrial DNA.</strong>
|
|
Neurology 42: 209-217, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1734306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1734306</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1734306" 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/10.1212/wnl.42.1.209" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Tyynismaa2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tyynismaa, H., Sun, R., Ahola-Erkkila, S., Almusa, H., Poyhonen, R., Korpela, M., Honkaniemi, J., Isohanni, P., Paetau, A., Wang, L., Suomalainen, A.
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<strong>Thymidine kinase 2 mutations in autosomal recessive progressive external ophthalmoplegia with multiple mitochondrial DNA deletions.</strong>
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Hum. Molec. Genet. 21: 66-75, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21937588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21937588</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21937588" 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/ddr438" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Wang1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wang, L., Munch-Petersen, B., Herrstrom Sjoberg, A., Hellman, U., Bergman, T., Jornvall, H., Eriksson, S.
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<strong>Human thymidine kinase 2: molecular cloning and characterisation of the enzyme activity with antiviral and cytostatic nucleoside substrates.</strong>
|
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FEBS Lett. 443: 170-174, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9989599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9989599</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9989599" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0014-5793(98)01711-6" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Wang2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wang, L., Saada, A., Eriksson, S.
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<strong>Kinetic properties of mutant human thymidine kinase 2 suggest a mechanism for mitochondrial DNA depletion myopathy.</strong>
|
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J. Biol. Chem. 278: 6963-6968, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12493767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12493767</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12493767" 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/10.1074/jbc.M206143200" 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="Willecke1977" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Willecke, K., Reber, T., Kucherlapati, R. S., Ruddle, F. H.
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<strong>Human mitochondrial thymidine kinase is coded for by a gene on chromosome 16 of the nucleus.</strong>
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Somat. Cell Genet. 3: 237-245, 1977.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/605384/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">605384</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=605384" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/BF01538743" target="_blank">Full Text</a>]
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</p>
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</div>
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</ol>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 11/11/2021
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 08/11/2016<br>Cassandra L. Kniffin - updated : 6/16/2015<br>Cassandra L. Kniffin - updated : 12/3/2014<br>Cassandra L. Kniffin - updated : 10/25/2012<br>Matthew B. Gross - updated : 10/24/2012<br>George E. Tiller - updated : 12/2/2011<br>Patricia A. Hartz - updated : 1/8/2010<br>Matthew B. Gross - updated : 11/3/2009<br>Patricia A. Hartz - updated : 10/12/2009<br>Cassandra L. Kniffin - updated : 8/7/2003<br>Victor A. McKusick - updated : 12/27/2002<br>Victor A. McKusick - updated : 10/19/2001<br>Rebekah S. Rasooly - updated : 4/9/1999<br>Jennifer P. Macke - updated : 3/16/1999
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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 : 6/2/1986
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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 : 06/17/2022
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 02/24/2022<br>carol : 11/11/2021<br>carol : 08/12/2016<br>ckniffin : 08/11/2016<br>carol : 06/22/2015<br>mcolton : 6/17/2015<br>ckniffin : 6/16/2015<br>alopez : 12/15/2014<br>mcolton : 12/12/2014<br>ckniffin : 12/3/2014<br>carol : 9/17/2013<br>carol : 11/5/2012<br>ckniffin : 10/25/2012<br>mgross : 10/24/2012<br>alopez : 12/2/2011<br>terry : 12/2/2011<br>carol : 12/21/2010<br>ckniffin : 12/9/2010<br>mgross : 5/26/2010<br>wwang : 1/8/2010<br>mgross : 11/3/2009<br>mgross : 11/3/2009<br>terry : 10/12/2009<br>carol : 9/20/2005<br>ckniffin : 8/31/2005<br>tkritzer : 8/12/2003<br>ckniffin : 8/7/2003<br>cwells : 1/2/2003<br>terry : 12/27/2002<br>alopez : 11/27/2001<br>alopez : 11/21/2001<br>cwells : 10/23/2001<br>cwells : 10/23/2001<br>terry : 10/19/2001<br>mgross : 4/12/1999<br>mgross : 4/9/1999<br>mgross : 3/17/1999<br>mgross : 3/16/1999<br>supermim : 3/16/1992<br>supermim : 3/20/1990<br>ddp : 10/27/1989<br>marie : 3/25/1988<br>reenie : 6/2/1986
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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> 188250
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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 KINASE, MITOCHONDRIAL; TK2
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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-text-font">
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<strong><em>HGNC Approved Gene Symbol: TK2</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 703527003;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 16q21
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Genomic coordinates <span class="small">(GRCh38)</span> : 16:66,508,003-66,550,291 </span>
|
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</em>
|
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</strong>
|
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<span class="small">(from NCBI)</span>
|
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</h4>
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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|
Phenotype <br /> MIM number
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</th>
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<th>
|
|
Inheritance
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</th>
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<th>
|
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="2">
|
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<span class="mim-font">
|
|
16q21
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
?Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
617069
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
Autosomal recessive
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
3
|
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</span>
|
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</td>
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</tr>
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<tr>
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<td>
|
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<span class="mim-font">
|
|
Mitochondrial DNA depletion syndrome 2 (myopathic type)
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
609560
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
Autosomal recessive
|
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</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
3
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
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</h4>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Thymidine kinase-2 (TK2) is a mitochondrial deoxyribonucleoside kinase that phosphorylates thymidine, deoxycytidine, and deoxyuridine, as well as antiviral and anticancer nucleoside analogs (Johansson and Karlsson, 1997). </p>
|
|
</span>
|
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<div>
|
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<br />
|
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
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<p>Johansson and Karlsson (1997) cloned cDNAs encoding human TK2. The gene encodes a 234-amino acid polypeptide. Although TK2 is believed to reside in mitochondria, it contains no mitochondrial translocation signal sequence. Northern blot analysis revealed that TK2 was ubiquitously expressed as 2 transcripts of 2.4 and 4 kb. Expression of the TK2 cDNA resulted in a 60-kD protein. </p><p>Based on the partial protein sequence of human TK2, Wang et al. (1999) isolated a human brain TK2 cDNA. Wang et al. (1999) noted that although the cDNA they isolated corresponds to the full-length mature protein, it is likely to be incomplete because it lacks the coding region for a mitochondrial target presequence. They reported that the predicted protein sequence matched that of purified TK2, but differed at the N terminus and at amino acid 28 from the TK2 sequence deduced by Johansson and Karlsson (1997). TK2 shares approximately 40% identity with deoxycytidine kinase (125450) and deoxyguanosine kinase (DGUOK; 601465) on the amino acid level. Northern blot analysis indicated that the TK2 gene was expressed as multiple transcripts, some of which show a tissue-specific pattern. The highest levels of expression were observed in testis and ovary. </p><p>By screening a human genomic BAC library with the TK2 cDNA reported by Wang et al. (1999), followed by database analysis, Wang et al. (2003) obtained a full-length TK2 cDNA. The deduced protein contains 265 amino acids and has an N-terminal mitochondrial leader sequence. </p><p>Sato et al. (2009) identified a number of TK2 splice variants that initiated in exons 8 or 9 and included further upstream exons. RT-PCR detected variable expression of TK2 upstream exons in a wide variety of tissues. </p><p>Gross (2009) noted that a revised sequence for TK2 (GenBank NP_004605.3) indicates that the full-length TK2 protein contains 307 amino acids. Behin et al. (2012) noted that the TK2 sequence had been revised again (GenBank NP_004605.4) and that the full-length 265-amino acid TK2 protein lacks 42 N-terminal amino acids found in the earlier sequence (GenBank NP_004605.3). </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 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>Johansson and Karlsson (1997) found that expression of the TK2 cDNA resulted in a protein with phosphorylation activity similar to purified human TK2. </p><p>Wang et al. (1999) characterized both recombinant and native TK2 forms and found that the enzyme has broad substrate specificity and complex kinetics, suggesting that it may play a role in the activation of chemotherapeutic nucleoside analogs. </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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<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>Saada et al. (2001) stated that the TK2 gene contains 10 exons. Sato et al. (2009) determined that the TK2 gene contains 16 exons, which are subject to extensive alternative splicing. </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>The gene for mitochondrial TK2 is on chromosome 16 (Willecke et al., 1977). Johansson and Karlsson (1997) found 2 STS markers in the TK2 cDNA that map to chromosome 16q22. The TK2 gene partially overlaps the BEAN gene (612051) on chromosome 16q22.1 and is transcribed in the opposite orientation (Sato et al., 2009). </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><strong><em>Autosomal Recessive Mitochondrial DNA Depletion Syndrome 2</em></strong></p><p>
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In 4 individuals with autosomal recessive mitochondrial DNA depletion syndrome-2 (MTDPS2; 609560), manifest as onset in infancy of severe myopathy, Saada et al. (2001) identified 2 mutations in the TK2 gene (188250.0001-188250.0002). In these individuals, the activity of TK2 in muscle mitochondria was reduced to 14 to 45% of the mean value in healthy control individuals. Mandel et al. (2001) identified mutations in the DGUOK gene in another form of mtDNA depletion syndrome, the hepatocerebral form (MTDPS3; 251880). They noted that the main supply of deoxynucleoside triphosphates (dNTPs) for mtDNA synthesis comes from the salvage pathway initiated by DGUOK and TK2. The association of mtDNA depletion with mutations in the genes encoding these 2 kinases suggested that the salvage pathway enzymes are involved in the maintenance of balanced mitochondrial dNTP pools. </p><p>Behin et al. (2012) identified homozygous or compound heterozygous TK2 mutations (188250.0003, 188250.0005, and 188250.0006) in 3 unrelated adult patients with a slowly progressive form of MTDPS2. All patients reported some form of hypotonia, early fatigue, or delayed walking in early childhood and 2 had proximal muscle weakness in childhood. Although muscle biopsies showed mtDNA depletion, there was higher residual mtDNA (about 30% of controls) compared to patients with a more severe form of the disorder (about 11% of controls). However, there were no apparent genotype/phenotype correlations. </p><p><strong><em>Autosomal Recessive Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions 3</em></strong></p><p>
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By exome sequencing, Tyynismaa et al. (2012) identified compound heterozygous missense mutations in the TK2 gene (188250.0007 and 188250.0008) in 2 Finnish sisters with adult-onset autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOB3; 617069). Tyynismaa et al. (2012) suggested that the higher residual activity of the mutants corresponded to the later onset and milder phenotypes in these patients compared to those with MTDPS2. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Akman et al. (2008) created mice harboring a his126-to-asn (H126N) mutation in the Tk2 gene. The orthologous mutation in humans (H163N; see 188250.0001) causes an early muscle-specific form of mtDNA depletion syndrome. Homozygous mutant mice (Tk2 -/-) were obtained at the expected mendelian frequency and appeared normal at birth. However, at postnatal day 10, they showed several defects relative to wildtype and heterozygous mutant littermates, including growth retardation, reduced spontaneous activity, generalized coarse tremor, and impaired gait. They rapidly developed weakness, leading to severe stress or death by 2 weeks of age. Tk2 -/- animals showed reduced Tk2 activity in all tissues analyzed, with activity reduced to 1.7% of wildtype in brain, the most severely affected tissue. In Tk2 -/- mice, brain mitochondria had a dTTP concentration about 20% of wildtype, and liver mitochondria showed reduced levels of both dTTP and dCTP. The content of other dNTPs in these tissues was unchanged, and dNTP levels in other tissues were not affected. Depletion of mtDNA was most prominent in brain, where it was 12.5% of wildtype, and only brain showed decreased activities of respiratory chain enzymes, primarily complexes I and IV, and reduced ATP levels and ATP/ADP ratios. Spinal cord neurons had abnormal vacuolar changes, and the white matter of spinal cord and cortex showed evidence of activated glial cells. Akman et al. (2008) concluded that, in contrast to the muscle-specific phenotype observed in patients with the H121N (now H163N) mutation, mice homozygous for the H126N mutation showed a rapidly progressive encephalomyelopathy. </p><p>Bartesaghi et al. (2010) demonstrated that in vivo loss of Tk2 activity in mice led to a severe ataxic phenotype, accompanied by reduced mtDNA copy number and decreased steady-state levels of electron transport chain proteins in the brain. In Tk2-deficient cerebellar neurons, these abnormalities were associated with impaired mitochondrial bioenergetic function, aberrant mitochondrial ultrastructure, and degeneration of selected neuronal types. </p><p>Lopez-Gomez et al. (2021) evaluated the effects of AAV gene therapy with and without pyrimidine deoxynucleoside (deoxycytidine (dC) and thymidine (dT)) treatment in a mouse model of Tk2 deficiency. AAV9 delivery of TK2 cDNA (AAV9-TK2) to the mutant mice on postnatal day 1 rescued Tk2 activity in liver, brain, and muscle but not in kidneys. The treated mutant mice had delayed disease onset and longer lifespan compared to untreated mutant mice. When the mice were treated with sequential AAV dosing, a dose of AAV9-TK2 on postnatal day 1 and then a dose of AAV2-TK2 on day 29, vector induction was not increased in the kidneys and vector genomes per nucleus were decreased in the brain and muscle compared to the mice treated with only AAV9-TK2. However, survival of the AAV9-TK2/AAV2-TK2 treated mice was significantly increased compared to the AAV9-TK2 treated and untreated mutant mice. Growth curves, motor function, and strength were similar in the AAV9-TK2/AAV2-TK2 treated mice and the AAV9-TK2 treated mice, and neither treatment cohort developed head tremors. The mutant mice were also treated with sequential AAV9-TK2/AAV2-TK2 dosing and with oral dC and dT from postnatal day 21 and had improved growth, survival, and mtDNA copy number in liver and kidneys compared to the other treatment cohorts of mutant mice. Lopez-Gomez et al. (2021) concluded that dC and dT supplementation enhances the effects of TK2 gene therapy and supports the potential for future combination therapy in patients with TK2 deficiency. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>8 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 MITOCHONDRIAL DNA DEPLETION SYNDROME 2 (MYOPATHIC 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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TK2, HIS121ASN
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<br />
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SNP: rs137854429,
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gnomAD: rs137854429,
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ClinVar: RCV000013545, RCV001386287, RCV004526595
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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>Based on the revised protein sequence for TK2 (GenBank NP_004605.4), the mutation designated HIS90ASN (H90N) and later HIS163ASN (H163N) is now referred to as HIS121ASN (H121N) (Behin et al., 2012). </p><p>In an Ashkenazi Jewish patient with mitochondrial DNA depletion syndrome-2 (MTDPS2; 609560), manifest as a myopathy, Saada et al. (2001) found a homozygous GC-to-AA substitution at nucleotides 267-268 of the TK2 gene, resulting in a his90-to-asn (HIS90ASN) substitution. The patient died at the age of 4 years. </p><p>Wang et al. (2003) found that recombinant human TK2 with the H121N mutation had a similar subunit structure compared with wildtype TK2. The H121N mutant enzyme had normal Km values for thymidine and deoxycytidine, but 2- and 3-fold lower Vmax values, respectively, compared with wildtype TK2 and markedly increased Km values for ATP, leading to decreased enzyme efficiency. Competition experiments revealed that thymidine and deoxycytidine interacted differently with the H121N mutant compared with wildtype TK2. </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>.0002 MITOCHONDRIAL DNA DEPLETION SYNDROME 2 (MYOPATHIC 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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TK2, ILE212ASN
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<br />
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SNP: rs137854430,
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ClinVar: RCV000013546, RCV003556012
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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>Based on the revised protein sequence for TK2 (GenBank NP_004605.4), the mutation designated ILE181ASN (I181N) and later ILE254ASN (I254N) is now referred to as ILE212ASN (I212N) (Behin et al., 2012). </p><p>In 3 Muslim-Arab infants with mitochondrial DNA depletion syndrome-2 (MTDPS2; 609560), manifest as a myopathy, Saada et al. (2001) found a T-to-A transversion at nucleotide 542 of the TK2 gene, resulting in an ile181-to-asn (ILE181ASN) substitution. Two of the patients were mechanically ventilated at age 3 years at the time of the report; a third had died at age 19 months. </p><p>Wang et al. (2003) found that recombinant human TK2 with the I212N mutation had a similar subunit structure compared with wildtype TK2. However, the I212N mutant enzyme showed less than 1% activity compared with wildtype TK2 with all deoxynucleosides. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 MITOCHONDRIAL DNA DEPLETION SYNDROME 2 (MYOPATHIC 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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TK2, THR108MET
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<br />
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SNP: rs137854431,
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gnomAD: rs137854431,
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ClinVar: RCV000013547, RCV000199738, RCV003883499, RCV003993743, RCV004757106
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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>Based on the revised protein sequence for TK2 (GenBank NP_004605.4), the mutation designated THR77MET (T77M) and later THR150MET (T150M) is now referred to as THR108MET (T108M) (Behin et al., 2012). </p><p>Mancuso et al. (2002) described 2 sibs with mitochondrial DNA depletion syndrome-2 (MTDPS2; 609560) who were compound heterozygous for the previously described H90N mutation (188250.0001) and a novel thr77-to-met (THR77MET) mutation. The proband was normal until 12 months of age when he developed frequent falls and progressive gait impairment, leading to inability to walk by age 26 months. By age 2 years he was unable to stand. He became dependent on mechanical ventilation by 3 years of age and died at 40 months of age. An older sister was similarly affected but with a more slowly evolving course. At age 16 months she began to have frequent falls, limb weakness, and gait abnormality, and by age 4 years she was no longer able to walk. She had elevated serum CK levels and lactic acidosis. </p><p>In a family originally described by Tritschler et al. (1992) in which 3 sibs had mitochondrial DNA depletion syndrome-2, Mancuso et al. (2003) identified homozygosity for the THR77MET mutation. The patients had 80 to 90% mitochondrial DNA depletion in muscle biopsy specimens, and all died of respiratory failure by age 40 months. The mutation is near the active site, in the alpha-4 helix of the protein, which is important for enzyme dimerization and nucleoside recognition. The authors noted that exon 5 is a hotspot for TK2 mutations. </p><p>Behin et al. (2012) reported 2 unrelated patients who were homozygous for the T108M mutation but who had had a milder course and slower progression than previously associated with this mutation. One patient had hypotonia since birth, delayed early walking, and proximal muscle weakness in childhood, whereas the other showed early fatigue in childhood; both presented in their early thirties with more significant impairment. Features included waddling gait, distal and proximal muscle weakness, axial weakness, and respiratory insufficiency. One patient was wheelchair-bound and the other could not walk for more than 15 minutes. More variable features included ptosis, hypophonia, and facial weakness. Cognition, hearing, and cardiac function were normal. EMG showed a myogenic pattern, and muscle biopsies showed dystrophic changes consistent with a mitochondrial myopathy, including deficiencies of complexes I, III, and IV. Muscle mtDNA depletion was apparent, with mtDNA levels at about 30% of normal controls. This report expanded the phenotypic spectrum of MTDPS2 to include patients with much slower progression, which may have been due to better preservation of residual muscle mtDNA compared to more severely affected patients. </p><p>Paradas et al. (2013) reported a 22-year-old man, born of consanguineous parents, with MTDPS2 due to a homozygous T108M mutation. He had normal development until age 24 months, when he showed proximal muscle weakness of the lower limbs resulting in a waddling gait. At age 20, he had a nasal voice and mild proximal arm weakness. After sudden onset of respiratory arrest triggered by pneumonia, he had rapid worsening of the muscle weakness and became wheelchair-bound. He had severe axial and proximal muscle weakness, facial weakness without ptosis, pectoral atrophy, scapular winging, and ankle contractures. He also had significant gynecomastia of unclear etiology. Laboratory studies showed increased serum creatine kinase and normal serum lactate. Muscle samples showed dystrophic features, endomysial fibrosis, abnormally shaped mitochondria, decreased mitochondrial complex I activity (35% of normal), and multiple mtDNA deletions (45% residual mtDNA). Family history revealed a 3-year-old sister who died of respiratory failure due to muscular dystrophy as well as 2 infant deaths in previous generations. The report was notable for significant intrafamilial phenotypic heterogeneity. Functional studies of the T108M variant were not performed. </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 MITOCHONDRIAL DNA DEPLETION SYNDROME 2 (MYOPATHIC TYPE)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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|
<span class="mim-text-font">
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|
|
|
TK2, ILE53MET
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<br />
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|
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SNP: rs137854432,
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|
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ClinVar: RCV000013548
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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>Based on the revised protein sequence for TK2 (GenBank NP_004605.4), the mutation designated ILE22MET (I22M) and later ILE95MET (I95M) is now referred to as ILE53MET (I53M) (Behin et al., 2012). </p><p>In a Hispanic family with nonconsanguineous parents, Mancuso et al. (2002) found that mitochondrial DNA depletion syndrome-2 (MTDPS2; 609560) is caused by homozygosity for an ile22-to-met (ILE22MET) mutation in the TK2 gene. A brother and sister were affected. The sister had severe weakness and hypotonia from the first months of life and died at the age of 2 years. Her brother was normal until the age of 15 months, when he developed increasing lumbar lordosis and waddling gait. Arm and cervical muscles were involved later. By the age of 2 years he had lost his ability to walk. At the age of 3 years, he had severe proximal limb weakness, muscle wasting, areflexia, and scoliosis. Results of nerve conduction studies were normal, but EMG showed chronic partial denervation, with fibrillations and severe loss of motor unit potentials. These electrophysiologic findings were compatible with spinal muscular atrophy. At the time of the study, he was still alive at age 4 years. The evidence of lower motor neuron disease was taken to indicate that the clinical expression of TK2 mutations is not limited to myopathy. </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 MITOCHONDRIAL DNA DEPLETION SYNDROME 2 (MYOPATHIC TYPE)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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TK2, 8-BP DUP
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<br />
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|
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SNP: rs281865502,
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gnomAD: rs281865502,
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ClinVar: RCV000032592
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In an adult man with slowly progressive mitochondrial DNA depletion syndrome-2 (MTDPS2; 609560), Behin et al. (2012) identified compound heterozygosity for 2 mutations in the TK2 gene: an 8-bp duplication in exon 1, resulting in a frameshift and premature termination (Trp4ValfsTer40), and a 268C-T transition in exon 4, resulting in an arg90-to-cys (R90C; 188250.0006) substitution in a region important for TK2 dimer stabilization. Each unaffected parent was heterozygous for 1 of the mutations. TK2 activity in patient fibroblasts was 4% of controls. The patient had mild ptosis at age 13 years, dysarthria at age 15, and proximal lower limb weakness at age 25. At age 31, he presented with ptosis, upper gaze limitation, hypophonia, axial and limb muscle weakness, and respiratory insufficiency, although he remained ambulatory. Laboratory investigations showed mild increased serum creatine kinase, and skeletal muscle biopsy showed mitochondrial defects with mtDNA depletion (about 30% residual mtDNA compared to controls). </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>.0006 MITOCHONDRIAL DNA DEPLETION SYNDROME 2 (MYOPATHIC 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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TK2, ARG90CYS
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<br />
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SNP: rs281865489,
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gnomAD: rs281865489,
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ClinVar: RCV000032241, RCV000522439, RCV002513294, RCV003492322
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the arg90-to-cys (R90C) mutation in the TK2 gene that was found in compound heterozygous state in a patient with slowly progressive mitochondrial DNA depletion syndrome-2 (MTDPS2; 609560) by Behin et al. (2012), see 188250.0005. </p>
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<span class="mim-font">
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<strong>.0007 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE 3 (1 family)</strong>
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</span>
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</h4>
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TK2, ARG225TRP
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<br />
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SNP: rs137886900,
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gnomAD: rs137886900,
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ClinVar: RCV000032251, RCV000239457, RCV001380377, RCV003230374
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<p>In 2 Finnish sisters with adult-onset autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOB3; 617069), Tyynismaa et al. (2012) identified compound heterozygous mutations in the TK2 gene: a c.673C-T transition, resulting in an arg225-to-trp (R225W) substitution, and a c.688A-G transition, resulting in a thr230-to-ala (T230A; 188250.0008) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were filtered against the dbSNP (build 130) and 1000 Genomes Project databases. The R225W mutation was not found in 400 Finnish control chromosomes, but the T230A mutation was found in 1 of 400 Finnish control chromosomes. Parental DNA was not available for segregation analysis. The mutated residues, while located within a highly conserved sequence block, are not themselves fully conserved, even among vertebrates. In vitro functional expression studies in E. coli showed that both mutant enzymes had higher Km and lower Vmax values compared to wildtype, resulting in decreased catalytic efficiencies (17-22% for T230A and 3-4% for R225W). Mitochondria isolated from both patients' cells showed TK2-specific activity between 22 and 54% of controls. Tyynismaa et al. (2012) suggested that the residual activity of the mutants corresponded to the later onset and milder phenotypes in these patients. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>.0008 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE 3 (1 family)</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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TK2, THR230ALA
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<br />
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SNP: rs281865495,
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gnomAD: rs281865495,
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ClinVar: RCV000239458, RCV001852646
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</span>
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</div>
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<span class="mim-text-font">
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<p>For discussion of the thr230-to-ala (T230A) mutation in the TK2 gene that was found in compound heterozygous state in 2 sisters with adult-onset autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOB3; 617069) by Tyynismaa et al. (2012), see 188250.0007. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<ol>
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<li>
|
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<p class="mim-text-font">
|
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Akman, H. O., Dorado, B., Lopez, L. C., Garcia-Cazorla, A., Vila, M. R., Tanabe, L. M., Dauer, W. T., Bonilla, E., Tanji, K., Hirano, M.
|
|
<strong>Thymidine kinase 2 (H126N) knockin mice show the essential role of balanced deoxynucleotide pools for mitochondrial DNA maintenance.</strong>
|
|
Hum. Molec. Genet. 17: 2433-2440, 2008.
|
|
|
|
|
|
[PubMed: 18467430]
|
|
|
|
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[Full Text: https://doi.org/10.1093/hmg/ddn143]
|
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</p>
|
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</li>
|
|
|
|
<li>
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<p class="mim-text-font">
|
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Bartesaghi, S., Betts-Henderson, J., Cain, K., Dinsdale, D., Zhou, X., Karlsson, A., Salomoni, P., Nicotera, P.
|
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<strong>Loss of thymidine kinase 2 alters neuronal bioenergetics and leads to neurodegeneration.</strong>
|
|
Hum. Molec. Genet. 19: 1669-1677, 2010.
|
|
|
|
|
|
[PubMed: 20123860]
|
|
|
|
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|
[Full Text: https://doi.org/10.1093/hmg/ddq043]
|
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</p>
|
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</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Behin, A., Jardel, C., Claeys, K. G., Fagart, J., Louha, M., Romero, N. B., Laforet, P., Eymard, B., Lombes, A.
|
|
<strong>Adult cases of mitochondrial DNA depletion due to TK2 defect: an expanding spectrum.</strong>
|
|
Neurology 78: 644-648, 2012.
|
|
|
|
|
|
[PubMed: 22345218]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1212/WNL.0b013e318248df2b]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
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Gross, M. B.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 11/3/2009.
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Johansson, M., Karlsson, A.
|
|
<strong>Cloning of the cDNA and chromosome localization of the gene for human thymidine kinase 2.</strong>
|
|
J. Biol. Chem. 272: 8454-8458, 1997.
|
|
|
|
|
|
[PubMed: 9079672]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1074/jbc.272.13.8454]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lopez-Gomez, C., Sanchez-Quintero, M. J., Lee, E. J., Kleiner, G., Tadesse, S., Xie, J., Akman, H. O., Gao, G., Hirano, M.
|
|
<strong>Synergistic deoxynucleoside and gene therapies for thymidine kinase 2 deficiency.</strong>
|
|
Ann. Neurol. 90: 640-652, 2021. Note: Erratum: Ann. Neurol. 91: 303 only, 2022.
|
|
|
|
|
|
[PubMed: 34338329]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ana.26185]
|
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</p>
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</li>
|
|
|
|
<li>
|
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<p class="mim-text-font">
|
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Mancuso, M., Filosto, M., Bonilla, E., Hirano, M., Shanske, S., Vu, T. H., DiMauro, S.
|
|
<strong>Mitochondrial myopathy of childhood associated with mitochondrial DNA depletion and a homozygous mutation (T77M) in the TK2 gene.</strong>
|
|
Arch. Neurol. 60: 1007-1009, 2003.
|
|
|
|
|
|
[PubMed: 12873860]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1001/archneur.60.7.1007]
|
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|
|
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</p>
|
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</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Mancuso, M., Salviati, L., Sacconi, S., Otaegui, D., Camano, P., Marina, A., Bacman, S., Moraes, C. T., Carlo, J. R., Garcia, M., Garcia-Alvarez, M., Monzon, L., Naini, A. B., Hirano, M., Bonilla, E., Taratuto, A. L., DiMauro, S., Vu, T. H.
|
|
<strong>Mitochondrial DNA depletion: mutations in thymidine kinase gene with myopathy and SMA.</strong>
|
|
Neurology 59: 1197-1202, 2002.
|
|
|
|
|
|
[PubMed: 12391347]
|
|
|
|
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|
[Full Text: https://doi.org/10.1212/01.wnl.0000028689.93049.9a]
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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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Mandel, H., Szargel, R., Labay, V., Elpeleg, O., Saada, A., Shalata, A., Anbinder, Y., Berkowitz, D., Hartman, C., Barak, M., Eriksson, S., Cohen, N.
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|
<strong>The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA.</strong>
|
|
Nature Genet. 29: 337-341, 2001. Note: Erratum: Nature Genet. 29: 491 only, 2001.
|
|
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|
|
|
[PubMed: 11687800]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng746]
|
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|
|
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|
</p>
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</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Paradas, C., Gutierrez Rios, P., Rivas, E., Carbonell, P., Hirano, M., DiMauro, S.
|
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<strong>TK2 mutation presenting as indolent myopathy.</strong>
|
|
Neurology 80: 504-506, 2013.
|
|
|
|
|
|
[PubMed: 23303857]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1212/WNL.0b013e31827f0ff7]
|
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|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Saada, A., Shaag, A., Mandel, H., Nevo, Y., Eriksson, S., Elpeleg, O.
|
|
<strong>Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy.</strong>
|
|
Nature Genet. 29: 342-344, 2001.
|
|
|
|
|
|
[PubMed: 11687801]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng751]
|
|
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|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Sato, N., Amino, T., Kobayashi, K., Asakawa, S., Ishiguro, T., Tsunemi, T., Takahashi, M., Matsuura, T., Flanigan, K. M., Iwasaki, S., Ishino, F., Saito, Y., and 9 others.
|
|
<strong>Spinocerebellar ataxia type 31 is associated with 'inserted' penta-nucleotide repeats containing (TGGAA)n.</strong>
|
|
Am. J. Hum. Genet. 85: 544-557, 2009.
|
|
|
|
|
|
[PubMed: 19878914]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.ajhg.2009.09.019]
|
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</p>
|
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</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
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Tritschler, H.-J., Andreetta, F., Moraes, C. T., Bonilla, E., Arnaudo, E., Danon, M. J., Glass, S., Zelaya, B. M., Vamos, E., Telerman-Toppet, N., Shanske, S., Kadenbach, B., DiMauro, S., Schon, E. A.
|
|
<strong>Mitochondrial myopathy of childhood associated with depletion of mitochondrial DNA.</strong>
|
|
Neurology 42: 209-217, 1992.
|
|
|
|
|
|
[PubMed: 1734306]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1212/wnl.42.1.209]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
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Tyynismaa, H., Sun, R., Ahola-Erkkila, S., Almusa, H., Poyhonen, R., Korpela, M., Honkaniemi, J., Isohanni, P., Paetau, A., Wang, L., Suomalainen, A.
|
|
<strong>Thymidine kinase 2 mutations in autosomal recessive progressive external ophthalmoplegia with multiple mitochondrial DNA deletions.</strong>
|
|
Hum. Molec. Genet. 21: 66-75, 2012.
|
|
|
|
|
|
[PubMed: 21937588]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddr438]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Wang, L., Munch-Petersen, B., Herrstrom Sjoberg, A., Hellman, U., Bergman, T., Jornvall, H., Eriksson, S.
|
|
<strong>Human thymidine kinase 2: molecular cloning and characterisation of the enzyme activity with antiviral and cytostatic nucleoside substrates.</strong>
|
|
FEBS Lett. 443: 170-174, 1999.
|
|
|
|
|
|
[PubMed: 9989599]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s0014-5793(98)01711-6]
|
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</p>
|
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</li>
|
|
|
|
<li>
|
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<p class="mim-text-font">
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Wang, L., Saada, A., Eriksson, S.
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<strong>Kinetic properties of mutant human thymidine kinase 2 suggest a mechanism for mitochondrial DNA depletion myopathy.</strong>
|
|
J. Biol. Chem. 278: 6963-6968, 2003.
|
|
|
|
|
|
[PubMed: 12493767]
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[Full Text: https://doi.org/10.1074/jbc.M206143200]
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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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Willecke, K., Reber, T., Kucherlapati, R. S., Ruddle, F. H.
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<strong>Human mitochondrial thymidine kinase is coded for by a gene on chromosome 16 of the nucleus.</strong>
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Somat. Cell Genet. 3: 237-245, 1977.
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[PubMed: 605384]
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[Full Text: https://doi.org/10.1007/BF01538743]
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 11/11/2021<br>Cassandra L. Kniffin - updated : 08/11/2016<br>Cassandra L. Kniffin - updated : 6/16/2015<br>Cassandra L. Kniffin - updated : 12/3/2014<br>Cassandra L. Kniffin - updated : 10/25/2012<br>Matthew B. Gross - updated : 10/24/2012<br>George E. Tiller - updated : 12/2/2011<br>Patricia A. Hartz - updated : 1/8/2010<br>Matthew B. Gross - updated : 11/3/2009<br>Patricia A. Hartz - updated : 10/12/2009<br>Cassandra L. Kniffin - updated : 8/7/2003<br>Victor A. McKusick - updated : 12/27/2002<br>Victor A. McKusick - updated : 10/19/2001<br>Rebekah S. Rasooly - updated : 4/9/1999<br>Jennifer P. Macke - updated : 3/16/1999
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Creation Date:
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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 : 6/2/1986
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carol : 06/17/2022<br>carol : 02/24/2022<br>carol : 11/11/2021<br>carol : 08/12/2016<br>ckniffin : 08/11/2016<br>carol : 06/22/2015<br>mcolton : 6/17/2015<br>ckniffin : 6/16/2015<br>alopez : 12/15/2014<br>mcolton : 12/12/2014<br>ckniffin : 12/3/2014<br>carol : 9/17/2013<br>carol : 11/5/2012<br>ckniffin : 10/25/2012<br>mgross : 10/24/2012<br>alopez : 12/2/2011<br>terry : 12/2/2011<br>carol : 12/21/2010<br>ckniffin : 12/9/2010<br>mgross : 5/26/2010<br>wwang : 1/8/2010<br>mgross : 11/3/2009<br>mgross : 11/3/2009<br>terry : 10/12/2009<br>carol : 9/20/2005<br>ckniffin : 8/31/2005<br>tkritzer : 8/12/2003<br>ckniffin : 8/7/2003<br>cwells : 1/2/2003<br>terry : 12/27/2002<br>alopez : 11/27/2001<br>alopez : 11/21/2001<br>cwells : 10/23/2001<br>cwells : 10/23/2001<br>terry : 10/19/2001<br>mgross : 4/12/1999<br>mgross : 4/9/1999<br>mgross : 3/17/1999<br>mgross : 3/16/1999<br>supermim : 3/16/1992<br>supermim : 3/20/1990<br>ddp : 10/27/1989<br>marie : 3/25/1988<br>reenie : 6/2/1986
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