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Entry
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- *174763 - POLYMERASE, DNA, GAMMA; POLG
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*174763</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#populationGenetics">Population 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 role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/174763">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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<a href="#contributors"><strong>Contributors</strong></a>
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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=ENSG00000140521;t=ENST00000268124" 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=5428" 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=174763" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000140521;t=ENST00000268124" 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_001126131,NM_002693" 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_002693" 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=174763" 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=01438&isoform_id=01438_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/POLG" 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/1399956,1438508,1644239,1658277,1706507,4505937,21779923,27502689,29791648,39980566,82698795,82698797,119622450,119622451,119622452,158255998,187171277,311347818,311347820,311347822,311347824,311347826,311347828,311347830,311347832,311347834,311347836,311347838,311347840,311347842,311347844,311347846,311347848,311347850,311347852,311347854,311347856,311347858,311347860,311347862,311347864,311347866,311347868,311347870,311347872,311347874,311347876,311347878,311347880,311347882,311347884,311347886,311347888,311347890,311347892,311347894,311347896,922055512,922055514,922055516,922055518,922055520,922055522,1523728800,1523728802,1523728804,1523728806,1523728808,1523728810" 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/P54098" 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=5428" 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=ENSG00000140521;t=ENST00000268124" 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=POLG" 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=POLG" 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+5428" 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/POLG" 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:5428" 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/5428" 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=chr15&hgg_gene=ENST00000268124.11&hgg_start=89316320&hgg_end=89334824&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:9179" 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/polg" 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=174763[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">
|
|
<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
|
|
</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=174763[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/POLG/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000140521" 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=POLG" 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=POLG" 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=POLG" 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=POLG&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/PA33500" 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:9179" 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/FBgn0004406.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:1196389" 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/POLG#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:1196389" 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/5428/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=5428" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00013258;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-060303-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
|
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" 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="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</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="mimCellLinesLinksFold" 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://catalog.coriell.org/Search?q=OmimNum:174763" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</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:5428" 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=POLG&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> 20415001, 699328003, 717266001<br />
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<strong>ICD10CM:</strong> G31.81<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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174763
|
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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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POLYMERASE, DNA, GAMMA; POLG
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</span>
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</h3>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="alternativeTitles" class="mim-anchor"></a>
|
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<div>
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<p>
|
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
|
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</div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
POLYMERASE, DNA, GAMMA-1; POLG1<br />
|
|
POLG, CATALYTIC SUBUNIT<br />
|
|
POLG-ALPHA; POLGA
|
|
</span>
|
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</h4>
|
|
</div>
|
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</div>
|
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=POLG" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">POLG</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/15/498?start=-3&limit=10&highlight=498">15q26.1</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr15:89316320-89334824&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'})">15:89,316,320-89,334,824</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=203700,613662,607459,157640,258450" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="5">
|
|
<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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Progressive external ophthalmoplegia, autosomal dominant 1
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Progressive external ophthalmoplegia, autosomal recessive 1
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PheneGene Graphics <span class="caret"></span>
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<li><a href="/graph/linear/174763" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/174763" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p><a href="#26" class="mim-tip-reference" title="Lestienne, P. <strong>Evidence for a direct role of the DNA polymerase gamma in the replication of the human mitochondrial DNA in vitro.</strong> Biochem. Biophys. Res. Commun. 146: 1146-1153, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3619920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3619920</a>] [<a href="https://doi.org/10.1016/0006-291x(87)90767-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3619920">Lestienne (1987)</a> provided evidence for a role of DNA polymerase gamma (POLG) in the replication of human mitochondrial DNA. <a href="#2" class="mim-tip-reference" title="Bertazzoni, U., Scovassi, A. I., Brun, G. M. <strong>Chick-embryo DNA polymerase gamma: identity of gamma-polymerases purified from nuclei and mitochondria.</strong> Europ. J. Biochem. 81: 237-248, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/563788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">563788</a>] [<a href="https://doi.org/10.1111/j.1432-1033.1977.tb11945.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="563788">Bertazzoni et al. (1977)</a> showed that the enzyme was present in both the nucleus and the mitochondria. Mitochondrial POLG is a homotetramer; see POLG2 (<a href="/entry/604983">604983</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=563788+3619920" 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 sequences of the S. cerevisiae and S. pombe Polg genes, <a href="#43" class="mim-tip-reference" title="Ropp, P. A., Copeland, W. C. <strong>Cloning and characterization of the human mitochondrial DNA polymerase, DNA polymerase gamma.</strong> Genomics 36: 449-458, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8884268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8884268</a>] [<a href="https://doi.org/10.1006/geno.1996.0490" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8884268">Ropp and Copeland (1996)</a> cloned the human and Drosophila POLG genes and a partial chicken Polg cDNA. The human POLG cDNA, isolated from a HeLa cell cDNA library, encodes a predicted 1,239-amino acid protein that is 78% identical to chicken Polg in the polymerase domain. Antibodies against the polymerase domain of human POLG detected a 140-kD mitochondrial protein on Western blots and immunoprecipitated a protein with POLG-like activity from mitochondrial extracts. The authors found a potentially unstable CAG repeat in the first exon of the human POLG gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8884268" 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="#68" class="mim-tip-reference" title="Zullo, S. J., Butler, L., Zahorchak, R. J., Macville, M., Wilkes, C., Merril, C. R. <strong>Localization by fluorescence in situ hybridization (FISH) of human mitochondrial polymerase gamma (POLG) to human chromosome band 15q24-q26, and of mouse mitochondrial polymerase gamma (Polg) to mouse chromosome band 7E, with confirmation by direct sequence analysis of bacterial artificial chromosomes (BACs).</strong> Cytogenet. Cell Genet. 78: 281-284, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9465903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9465903</a>] [<a href="https://doi.org/10.1159/000134672" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9465903">Zullo et al. (1997)</a> identified cloned cDNA and genomic sequences as human mitochondrial POLG by homology with the catalytic subunit of yeast mitochondrial DNA polymerase. <a href="#25" class="mim-tip-reference" title="Lecrenier, N., van der Bruggen, P., Foury, F. <strong>Mitochondrial DNA polymerases from yeast to man: a new family of polymerases.</strong> Gene 185: 147-152, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9034326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9034326</a>] [<a href="https://doi.org/10.1016/s0378-1119(96)00663-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9034326">Lecrenier et al. (1997)</a> cloned a human POLG cDNA by searching for ESTs with homology to yeast Polg (Mip1p). The human and yeast POLG proteins are 43% identical. Human POLG is expressed as a 4.5- to 5.0-kb mRNA that is most abundant in skeletal muscle and heart. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9465903+9034326" 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>POLG Alternative Reading Frame</em></strong></p><p>
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<a href="#27" class="mim-tip-reference" title="Loughran, G., Zhdanov, A. V., Mikhaylova, M. S., Rozov, F. N., Datskevich, P. N., Kovalchuk, S. I., Serebryakova, M. V., Kiniry, S. J., Michel, A. M., O'Connor, P. B. F., Papkovsky, D. B., Atkins, J. F., Baranov, P. V., Shatsky, I. N., Andreev, D. E. <strong>Unusually efficient CUG initiation of an overlapping reading frame in POLG mRNA yields novel protein POLGARF.</strong> Proc. Nat. Acad. Sci. 117: 24936-24946, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32958672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32958672</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32958672[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/10.1073/pnas.2001433117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32958672">Loughran et al. (2020)</a> determined that the POLG mRNA is a dual-coding mRNA that encodes both POLG and POLGARF (<a href="/entry/620759">620759</a>). The POLGARF alternative reading frame (-1), which overlaps extensively with the POLG reading frame, is initiated by a CUG triplet 52 nucleotides upstream of the POLG start codon and produces a 260-amino acid POLGARF protein. The 5-prime leader of the POLG mRNA contains a 23-codon conserved AUG-initiated upstream ORF (uORF), and translation of this uORF governs the ratio between POLG and POLGARF synthesized from the single POLG mRNA. For further information on POLGARF, see <a href="/entry/620759">620759</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32958672" 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 POLG protein is composed of a C-terminal polymerase ('pol') domain and an amino-terminal exonuclease ('exo') domain. The exo domain increases the fidelity of mitochondrial DNA replication by conferring a proofreading activity to the enzyme (<a href="#23" class="mim-tip-reference" title="Lamantea, E., Tiranti, V., Bordoni, A., Toscano, A., Bono, F., Servidei, S., Papadimitriou, A., Spelbrink, H., Silvestri, L., Casari, G., Comi, G. P., Zeviani, M. <strong>Mutations of mitochondrial DNA polymerase gamma-A are a frequent cause of autosomal dominant or recessive progressive external ophthalmoplegia.</strong> Ann. Neurol. 52: 211-219, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12210792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12210792</a>] [<a href="https://doi.org/10.1002/ana.10278" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12210792">Lamantea et al., 2002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12210792" 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>Mitochondrial nucleoids are large complexes containing, on average, 5 to 7 mtDNA genomes and several proteins involved in mtDNA replication and transcription, as well as related processes. <a href="#4" class="mim-tip-reference" title="Bogenhagen, D. F., Rousseau, D., Burke, S. <strong>The layered structure of human mitochondrial DNA nucleoids.</strong> J. Biol. Chem. 283: 3665-3675, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18063578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18063578</a>] [<a href="https://doi.org/10.1074/jbc.M708444200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18063578">Bogenhagen et al. (2008)</a> had previously shown that POLG was associated with native purified HeLa cell nucleoids. Using a formaldehyde crosslinking technique, they found that POLG copurified with mtDNA and was a core nucleoid protein. <a href="#4" class="mim-tip-reference" title="Bogenhagen, D. F., Rousseau, D., Burke, S. <strong>The layered structure of human mitochondrial DNA nucleoids.</strong> J. Biol. Chem. 283: 3665-3675, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18063578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18063578</a>] [<a href="https://doi.org/10.1074/jbc.M708444200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18063578">Bogenhagen et al. (2008)</a> confirmed these findings by Western blot analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18063578" 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="#49" class="mim-tip-reference" title="Shestakova, E. D., Tumbinsky, R. S., Andreev, D. E., Rozov, F. N., Shatsky, I. N., Terenin, I. M. <strong>The roles of eIF4G2 in leaky scanning and reinitiation on the human dual-coding POLG mRNA.</strong> Int. J. Molec. Sci. 24: 17149, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38138978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38138978</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=38138978[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.3390/ijms242417149" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38138978">Shestakova et al. (2023)</a> noted that EIF4G2 (<a href="/entry/602325">602325</a>) promotes translation of mRNAs with long 5-prime leaders and uORFs via reinitiation after uORF translation or by substituting for EIF4G1 (<a href="/entry/600495">600495</a>) to promote leaky scanning through the translated uORF after loss of EIF4G1. They found that the uORF in the POLG/POLGARF mRNA made translation of both POLG and POLGARF reliant on EIF4G2. EIF4G2 enhanced both leaky scanning and reinitiation, and it appeared that ribosomes could acquire EIF4G2 during the early steps of reinitiation. <a href="#49" class="mim-tip-reference" title="Shestakova, E. D., Tumbinsky, R. S., Andreev, D. E., Rozov, F. N., Shatsky, I. N., Terenin, I. M. <strong>The roles of eIF4G2 in leaky scanning and reinitiation on the human dual-coding POLG mRNA.</strong> Int. J. Molec. Sci. 24: 17149, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38138978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38138978</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=38138978[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.3390/ijms242417149" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38138978">Shestakova et al. (2023)</a> concluded that EIF4G2 is a multifunctional scanning guardian that replaces EIF4G1 to facilitate ribosome movement but not ribosome attachment to mRNAs with uORFs, like POLG/POLGARF. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38138978" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By FISH, <a href="#68" class="mim-tip-reference" title="Zullo, S. J., Butler, L., Zahorchak, R. J., Macville, M., Wilkes, C., Merril, C. R. <strong>Localization by fluorescence in situ hybridization (FISH) of human mitochondrial polymerase gamma (POLG) to human chromosome band 15q24-q26, and of mouse mitochondrial polymerase gamma (Polg) to mouse chromosome band 7E, with confirmation by direct sequence analysis of bacterial artificial chromosomes (BACs).</strong> Cytogenet. Cell Genet. 78: 281-284, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9465903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9465903</a>] [<a href="https://doi.org/10.1159/000134672" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9465903">Zullo et al. (1997)</a> mapped the POLG gene to 15q24-q26 and the mouse Polg gene to chromosome 7. <a href="#65" class="mim-tip-reference" title="Walker, R. L., Anziano, P., Meltzer, P. S. <strong>A PAC containing the human mitochondrial DNA polymerase gamma gene (POLG) maps to chromosome 15q25.</strong> Genomics 40: 376-378, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9119411/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9119411</a>] [<a href="https://doi.org/10.1006/geno.1996.4580" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9119411">Walker et al. (1997)</a> mapped the POLG gene to 15q25 by FISH. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9465903+9119411" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#7" class="mim-tip-reference" title="Del Bo, R., Bordoni, A., Sciacco, M., Di Fonzo, A., Galbiati, S., Crimi, M., Bresolin, N., Comi, G. P. <strong>Remarkable infidelity of polymerase gamma-A associated with mutations in POLG1 exonuclease domain.</strong> Neurology 61: 903-908, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14557557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14557557</a>] [<a href="https://doi.org/10.1212/01.wnl.0000092303.13864.be" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14557557">Del Bo et al. (2003)</a> presented evidence suggesting that mutations in the exonuclease domain of POLG, which is responsible for the proofreading activity of the protein, result in a high frequency of rare, randomly distributed mtDNA point mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14557557" 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="#46" class="mim-tip-reference" title="Rovio, A., Tiranti, V., Bednarz, A. L., Suomalainen, A., Spelbrink, J. N., Lecrenier, N., Melberg, A., Zeviani, M., Poulton, J., Foury, F., Jacobs, H. T. <strong>Analysis of the trinucleotide CAG repeat from the human mitochondrial DNA polymerase gene in healthy and diseased individuals.</strong> Europ. J. Hum. Genet. 7: 140-146, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10196696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10196696</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200244" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10196696">Rovio et al. (1999)</a> demonstrated that the common allele for the trinucleotide CAG repeat within the coding sequence of the POLG gene is 10 CAG repeats. This allele is found in different ethnic groups at a uniformly high frequency (0.88) and is absent in only approximately 1% of individuals, suggesting that it may be maintained by selection. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10196696" 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="#53" class="mim-tip-reference" title="Tang, S., Wang, J., Lee, N.-C., Milone, M., Halberg, M. C., Schmitt, E. S., Craigen, W. J., Zhang, W., Wong, L.-J. C. <strong>Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum.</strong> J. Med. Genet. 48: 669-681, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21880868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21880868</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100222" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21880868">Tang et al. (2011)</a> identified mutations in the POLG gene in 136 (5%) of 2,697 patients analyzed because of a wide range of clinical features suggestive of a POLG-related disorder, including lactic acidosis, seizures, ataxia, peripheral neuropathy, developmental delay, myopathy, chronic progressive external ophthalmoplegia, or hepatopathy. Ninety-two patients had biallelic mutations, 3 had heterozygous dominant mutations, and 41 had 1 heterozygous mutation with a second mutant allele unidentified. A467T (<a href="#0002">174763.0002</a>) was the most common mutation, accounting for 23% of mutant alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21880868" 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="#52" class="mim-tip-reference" title="Stumpf, J. D., Bailey, C. M., Spell, D., Stillwagon, M., Anderson, K. S., Copeland, W. C. <strong>mip1 containing mutations associated with mitochondrial disease causes mutagenesis and depletion of mtDNA in Saccharomyces cerevisiae.</strong> Hum. Molec. Genet. 19: 2123-2133, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20185557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20185557</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20185557[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/ddq089" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20185557">Stumpf et al. (2010)</a> identified dominant and recessive changes in mtDNA mutagenesis and depletion and mitochondrial dysfunction caused by 31 mutations in the conserved regions of the mip1 gene, which encodes the Saccharomyces cerevisiae ortholog of human POLG. Twenty mip1 mutant enzymes were shown to disrupt mtDNA replication, implicating their orthologous human mutations in disease. Five theretofore uncharacterized sporadic POLG mutations caused decreased polymerase activity leading to mtDNA depletion and mitochondrial dysfunction. Most mitochondrial-defective mip1 mutants displayed reduced or depleted mtDNA, and the severity of the phenotype of the mip1 mutant strain correlated with the age of onset of disease associated with the human ortholog. Increasing nucleotide pools by overexpression of ribonucleotide reductase (RNR1; <a href="/entry/180450">180450</a>) suppressed mtDNA replication defects caused by several dominant mip1 mutations, and the orthologous human mutations revealed severe nucleotide binding defects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20185557" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Kang, Y., Hepojoki, J., Maldonado, R. S., Mito, T., Terzioglu, M., Manninen, T., Kant, R., Singh, S., Othman, A., Verma, R., Uusimaa, J., Wartiovaara, K., Kareinen, L., Zamboni, N., Nyman, T. A., Paetau, A., Kipar, A., Vapalahti, O., Suomalainen, A. <strong>Ancestral allele of DNA polymerase gamma modifies antiviral tolerance.</strong> Nature 628: 844-853, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38570685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38570685</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=38570685[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/10.1038/s41586-024-07260-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38570685">Kang et al. (2024)</a> investigated the role of the W748S mutation in the POLG1 gene in response to viral infection. Fibroblasts from patients with homozygosity for the W748S mutation were exposed to double-stranded RNA (dsRNA) and double-stranded DNA (dsDNA), which were used as a mimic of pathogenic-associated molecular patterns of viruses. Patient fibroblasts displayed a dampened interferon-beta response and an exaggerated proinflammatory response compared to control cells. Furthermore, patient fibroblasts had reduced mtDNA and mtRNA in the cell cytoplasm after dsDNA and dsRNA exposure compared to controls. Exposure of patient cells to the HSV1 virus resulted in enhanced expression of an early regulatory protein of HSV1 (ICP27), decreased POLG1 protein levels, decreased mtDNA levels, a dampened interferon response, and induction of phosphorylated MLKL, which activates necroptosis. Exposure of patient cells to the tick-born encephalitis virus (TBEV) and SARS-CoV-2 viruses also resulted in decreased POLG1 protein expression and increased phosphorylated MLKL, but an exaggerated interferon response. <a href="#18" class="mim-tip-reference" title="Kang, Y., Hepojoki, J., Maldonado, R. S., Mito, T., Terzioglu, M., Manninen, T., Kant, R., Singh, S., Othman, A., Verma, R., Uusimaa, J., Wartiovaara, K., Kareinen, L., Zamboni, N., Nyman, T. A., Paetau, A., Kipar, A., Vapalahti, O., Suomalainen, A. <strong>Ancestral allele of DNA polymerase gamma modifies antiviral tolerance.</strong> Nature 628: 844-853, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38570685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38570685</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=38570685[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/10.1038/s41586-024-07260-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38570685">Kang et al. (2024)</a> concluded that the W748S mutation in POLG1 results in an abnormal immune response to 3 different viruses favoring viral replication in the early infection phase, a delayed, overactivated proinflammatory response, and increased sensitivity to necroptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38570685" 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>Progressive External Ophthalmoplegia (PEO) with Mitochondrial DNA Deletions</em></strong></p><p>
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<a href="#57" class="mim-tip-reference" title="Van Goethem, G., Dermaut, B., Lofgren, A., Martin, J.-J., Van Broeckhoven, C. <strong>Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions.</strong> Nature Genet. 28: 211-212, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431686/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431686</a>] [<a href="https://doi.org/10.1038/90034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431686">Van Goethem et al. (2001)</a> identified a missense mutation (Y955C; <a href="#0001">174763.0001</a>) in the polymerase motif B of the POLG gene in a family segregating autosomal dominant progressive external ophthalmoplegia (PEOA1; <a href="/entry/157640">157640</a>). A tyrosine at position 955 is highly conserved in DNA polymerases of different species, including the orthologous enzymes in yeast and Drosophila. In 2 families with evidence of autosomal recessive PEO (PEOB1; <a href="/entry/258450">258450</a>), <a href="#57" class="mim-tip-reference" title="Van Goethem, G., Dermaut, B., Lofgren, A., Martin, J.-J., Van Broeckhoven, C. <strong>Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions.</strong> Nature Genet. 28: 211-212, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431686/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431686</a>] [<a href="https://doi.org/10.1038/90034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431686">Van Goethem et al. (2001)</a> found compound heterozygosity for 2 different missense mutations (see <a href="#0002">174763.0002</a>-<a href="#0004">174763.0004</a>) in the POLG gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11431686" 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="#60" class="mim-tip-reference" title="Van Goethem, G., Martin, J. J., Dermaut, B., Lofgren, A., Wibail, A., Ververken, D., Tack, P., Dehaene, I., Van Zandijcke, M., Moonen, M., Ceuterick, C., De Jonghe, P., Van Broeckhoven, C. <strong>Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia.</strong> Neuromusc. Disord. 13: 133-142, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12565911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12565911</a>] [<a href="https://doi.org/10.1016/s0960-8966(02)00216-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12565911">Van Goethem et al. (2003)</a> reported compound heterozygosity for 2 mutations in the POLG gene (A467T, <a href="#0002">174763.0002</a> and R627W, <a href="#0005">174763.0005</a>) in a patient with the clinical triad of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO; <a href="/entry/607459">607459</a>). The finding indicated that SANDO is a variant of autosomal recessive PEO. <a href="#66" class="mim-tip-reference" title="Winterthun, S., Ferrari, G., He, L., Taylor, R. W., Zeviani, M., Turnbull, D. M., Engelsen, B. A., Moen, G., Bindoff, L. A. <strong>Autosomal recessive mitochondrial ataxic syndrome due to mitochondrial polymerase-gamma mutations.</strong> Neurology 64: 1204-1208, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15824347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15824347</a>] [<a href="https://doi.org/10.1212/01.WNL.0000156516.77696.5A" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15824347">Winterthun et al. (2005)</a> identified homozygosity for the A467T mutation in affected members from 2 families with a form of SANDO characterized by early onset of migraine headaches and/or seizures, and the later development of myoclonus (see SCAE, <a href="/entry/607459">607459</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12565911+15824347" 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>POLG1 is the only polymerase known to be involved in replication of mtDNA. <a href="#19" class="mim-tip-reference" title="Kollberg, G., Jansson, M., Perez-Bercoff, A., Melberg, A., Lindberg, C., Holme, E., Moslemi, A.-R., Oldfors, A. <strong>Low frequency of mtDNA point mutations in patients with PEO associated with POLG1 mutations.</strong> Europ. J. Hum. Genet. 13: 463-469, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15702133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15702133</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15702133">Kollberg et al. (2005)</a> investigated whether mtDNA point mutations are involved, directly or indirectly, in the pathogenesis of PEO. Muscle biopsy specimens from patients with POLG1 mutations, affecting either the exonuclease or the polymerase domain, were investigated. Long-range PCR revealed multiple mtDNA deletions in all the patients but not in controls. No point mutations were identified in single COX-deficient muscle fibers. Cloning and sequencing of muscle homogenate identified randomly distributed point mutations at a very low frequency in patients and controls. <a href="#19" class="mim-tip-reference" title="Kollberg, G., Jansson, M., Perez-Bercoff, A., Melberg, A., Lindberg, C., Holme, E., Moslemi, A.-R., Oldfors, A. <strong>Low frequency of mtDNA point mutations in patients with PEO associated with POLG1 mutations.</strong> Europ. J. Hum. Genet. 13: 463-469, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15702133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15702133</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15702133">Kollberg et al. (2005)</a> concluded that mtDNA point mutations are not directly or indirectly involved in the pathogenesis of mitochondrial disease in patients with different POLG1 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15702133" 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="Gonzalez-Vioque, E., Blazquez, A., Fernandez-Moreira, D., Bornstein, B., Bautista, J., Arpa, J., Navarro, C., Campos, Y., Fernandez-Moreno, M. A., Garesse, R., Arenas, J., Martin, M. A. <strong>Association of novel POLG mutations and multiple mitochondrial DNA deletions with variable clinical phenotypes in a Spanish population.</strong> Arch. Neurol. 63: 107-111, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16401742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16401742</a>] [<a href="https://doi.org/10.1001/archneur.63.1.107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16401742">Gonzalez-Vioque et al. (2006)</a> identified mutations in the POLG gene in 6 (25%) of 24 patients with mitochondrial disease and muscle mtDNA deletions. Five patients had PEO; however, 1 patient, who had a mutation which was previously reported as a polymorphism, showed only mild distal muscle atrophy without ophthalmoplegia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16401742" 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="Hudson, G., Deschauer, M., Taylor, R. W., Hanna, M. G., Fialho, D., Schaefer, A. M., He, L.-P., Blakely, E., Turnbull, D. M., Chinnery, P. F. <strong>POLG1, C10ORF2, and ANT1 mutations are uncommon in sporadic progressive external ophthalmoplegia with multiple mitochondrial DNA deletions.</strong> Neurology 66: 1439-1441, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16682683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16682683</a>] [<a href="https://doi.org/10.1212/01.wnl.0000210486.32196.24" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16682683">Hudson et al. (2006)</a> identified mutations in the POLG gene in 3 (8%) of 38 patients with sporadic PEO. No mutations were identified in the ANT1 (<a href="/entry/103220">103220</a>) or C10ORF2 (<a href="/entry/606075">606075</a>) genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16682683" 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>Mitochondrial DNA Depletion Syndrome 4A (Alpers Type)</em></strong></p><p>
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<a href="#36" class="mim-tip-reference" title="Naviaux, R. K., Nguyen, K. V. <strong>POLG mutations associated with Alpers' syndrome and mitochondrial DNA depletion.</strong> Ann. Neurol. 55: 706-712, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15122711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15122711</a>] [<a href="https://doi.org/10.1002/ana.20079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15122711">Naviaux and Nguyen (2004)</a> reported 3 patients with mitochondrial DNA depletion syndrome-4A (MTDPS4A; <a href="/entry/203700">203700</a>), manifest as Alpers syndrome, who were homozygous for a mutation (E873X; <a href="#0008">174763.0008</a>) in the POLG gene. They later published a correction (<a href="#37" class="mim-tip-reference" title="Naviaux, R. K., Nguyen, K. V. <strong>POLG mutations associated with Alpers syndrome and mitochondrial DNA depletion. (Letter)</strong> Ann. Neurol. 58: 491 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16130100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16130100</a>] [<a href="https://doi.org/10.1002/ana.20544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16130100">Naviaux and Nguyen, 2005</a>) stating that 2 affected patients from 1 family with Alpers syndrome were compound heterozygous for 2 mutations in the POLG gene: E873X and A467T (<a href="#0002">174763.0002</a>). <a href="#37" class="mim-tip-reference" title="Naviaux, R. K., Nguyen, K. V. <strong>POLG mutations associated with Alpers syndrome and mitochondrial DNA depletion. (Letter)</strong> Ann. Neurol. 58: 491 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16130100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16130100</a>] [<a href="https://doi.org/10.1002/ana.20544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16130100">Naviaux and Nguyen (2005)</a> stated that the existence of a common 4-bp insertion in the POLG gene yielded the incorrect initial results. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16130100+15122711" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 4 patients with mtDNA depletion syndrome-4A, manifest as Alpers syndrome, <a href="#6" class="mim-tip-reference" title="Davidzon, G., Mancuso, M., Ferraris, S., Quinzii, C., Hirano, M., Peters, H. L., Kirby, D., Thorburn, D. R., DiMauro, S. <strong>POLG mutations and Alpers syndrome.</strong> Ann. Neurol. 57: 921-924, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15929042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15929042</a>] [<a href="https://doi.org/10.1002/ana.20498" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15929042">Davidzon et al. (2005)</a> identified compound heterozygosity for 2 mutations in the POLG gene (<a href="#0006">174763.0006</a> and <a href="#0013">174763.0013</a>). Liver biopsies from 3 patients showed mitochondrial DNA depletion ranging from 87 to 94%, and all 4 patients showed decreased activity of mtDNA-encoded respiratory chain complexes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15929042" 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="Ferrari, G., Lamantea, E., Donati, A., Filosto, M., Briem, E., Carrara, F., Parini, R., Simonati, A., Santer, R., Zeviani, M. <strong>Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-gamma A.</strong> Brain 128: 723-731, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15689359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15689359</a>] [<a href="https://doi.org/10.1093/brain/awh410" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15689359">Ferrari et al. (2005)</a> identified mutations in the POLG gene in 8 patients with Alpers syndrome and 1 patient with a nonspecific severe floppy infant syndrome associated with liver failure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15689359" 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>Mitochondrial DNA Depletion Syndrome 4B (MNGIE Type)</em></strong></p><p>
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In 2 sisters with mitochondrial DNA depletion syndrome-4B (MTDPS4B; <a href="/entry/613662">613662</a>), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) (<a href="#64" class="mim-tip-reference" title="Vissing, J., Ravn, K., Danielsen, E. R., Duno, M., Wibrand, F., Wevers, R. A., Schwartz, M. <strong>Multiple mtDNA deletions with features of MNGIE.</strong> Neurology 59: 926-929, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12297582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12297582</a>] [<a href="https://doi.org/10.1212/wnl.59.6.926" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12297582">Vissing et al., 2002</a>), <a href="#62" class="mim-tip-reference" title="Van Goethem, G., Schwartz, M., Lofgren, A., Dermaut, B., Van Broeckhoven, C., Vissing, J. <strong>Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy.</strong> Europ. J. Hum. Genet. 11: 547-549, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12825077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12825077</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12825077">Van Goethem et al. (2003)</a> identified 3 mutations in the POLG gene: T251I (<a href="#0007">174763.0007</a>), P587L (<a href="#0011">174763.0011</a>), and N864S (<a href="#0012">174763.0012</a>). The N864S mutation was in trans with the other 2 mutations; segregation in the family was consistent with the recessive nature of the 3 mutations, with the 2 sisters being compound heterozygotes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12825077+12297582" 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 infant with severe hypotonia, gastrointestinal dysmotility, and mtDNA depletion in muscle, <a href="#11" class="mim-tip-reference" title="Giordano, C., Powell, H., Leopizzi, M., De Curtis, M., Travaglini, C., Sebastiani, M., Gallo, P., Taylor, R. W., d'Amati, G. <strong>Fatal congenital myopathy and gastrointestinal pseudo-obstruction due to POLG1 mutations.</strong> Neurology 72: 1103-1105, 2009. Note: Erratum: Neurology 73: 738 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19307547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19307547</a>] [<a href="https://doi.org/10.1212/01.wnl.0000345002.47396.e1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19307547">Giordano et al. (2009)</a> identified compound heterozygosity for 2 mutations in the POLG gene (G848S, <a href="#0006">174763.0006</a> and R227W, <a href="#0021">174763.0021</a>). Other features included hearing loss and clubfoot. Brain MRI showed enlarged ventricles, but leukoencephalopathy was not noted. The patient died at age 20 days from respiratory failure. There was no liver damage aside from that resulting from parenteral nutrition. Analysis of the bowel showed that mtDNA depletion was confined mainly to the external layer of the muscularis propria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19307547" 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>Associations Pending Confirmation</em></strong></p><p>
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<a href="#45" class="mim-tip-reference" title="Rovio, A. T., Marchington, D. R., Donat, S., Schuppe, H.-S., Abel, J., Fritsche, E., Elliott, D. J., Laippala, P., Ahola, A. L., McNay, D., Harrison, R. F., Hughes, B., and 13 others. <strong>Mutations at the mitochondrial DNA polymerase (POLG) locus associated with male infertility.</strong> Nature Genet. 29: 261-262, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11687794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11687794</a>] [<a href="https://doi.org/10.1038/ng759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11687794">Rovio et al. (2001)</a> genotyped infertile and control males for POLG CAG-repeat lengths. Using sperm DNA from persons in whom azoospermia was excluded, they found 9 of 99 infertile males (9%) from Finland or England to be homozygous for the absence of the 10 CAG repeat common allele. In contrast, the common allele was present in sperm DNA from all 98 fertile males studied, as well as in all but 6 of 522 healthy controls whose blood DNA was analyzed in parallel. Based on standard Hardy-Weinberg predictions, the 'homozygous mutant' genotype (absence of the common allele, whether or not this reflected homozygosity for a particular mutant allele) should be found in approximately 1.7% of individuals. They found the genotype at a frequency slightly below expectation in the general population, although this deviation was not statistically significant. In contrast, their finding that the 'homozygous mutant' genotype occurred in 9 of 99 infertile but 0 of 98 fertile males was highly significant. They also found a higher frequency of heterozygosity in infertile males (35%) than in fertile males (18%) or in the general population (23%). Some infertile males may be compound heterozygotes, with a second mutation elsewhere in the gene. Infertile males homozygous for the POLG mutant genotype were below the commonly accepted thresholds for at least 2 out of 3 sperm quality parameters. The POLG genotype in blood and sperm was similar in these individuals, thus excluding any effect of de novo tissue-specific mutation. Polyglutamine tracts are commonly regarded as interfaces for protein-protein interactions; thus, a sperm-specific protein could interact with this region of POLG. Given the many rounds of cell division during spermatogenesis and the functional necessity of mtDNA for sperm function, it seems plausible that a suboptimal mtDNA polymerase could result in the accumulation of mtDNA mutations and in failure to complete differentiation. The mutant allele had 11 CAG repeats as the nodal frequency (see Fig. 1 of <a href="#45" class="mim-tip-reference" title="Rovio, A. T., Marchington, D. R., Donat, S., Schuppe, H.-S., Abel, J., Fritsche, E., Elliott, D. J., Laippala, P., Ahola, A. L., McNay, D., Harrison, R. F., Hughes, B., and 13 others. <strong>Mutations at the mitochondrial DNA polymerase (POLG) locus associated with male infertility.</strong> Nature Genet. 29: 261-262, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11687794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11687794</a>] [<a href="https://doi.org/10.1038/ng759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11687794">Rovio et al. (2001)</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11687794" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of 195 infertile patients and 190 normospermic men of Italian origin, <a href="#20" class="mim-tip-reference" title="Krausz, C., Guarducci, E., Becherini, L., degl'Innocenti, S., Gerace, L., Balercia, G., Forti, G. <strong>The clinical significance of the POLG gene polymorphism in male infertility.</strong> J. Clin. Endocr. Metab. 89: 4292-4297, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15356024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15356024</a>] [<a href="https://doi.org/10.1210/jc.2004-0008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15356024">Krausz et al. (2004)</a> found the 10 CAG repeat allele of the POLG gene in 85% of infertile and 81% of fertile controls. Mean values of sperm parameters such as sperm count, motility, and morphology did not differ significantly between repeat allele carriers and controls. The authors concluded that their study failed to confirm any influence of the POLG gene polymorphism on the efficiency of spermatogenesis and that analysis of the CAG repeat tract of the POLG gene does not appear to have any clinical diagnostic value. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15356024" 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 most severe manifestations of defects of the POLG protein have been associated with mutations of the 'spacer' region of POLG. <a href="#31" class="mim-tip-reference" title="Luoma, P. T., Luo, N., Loscher, W. N., Farr, C. L., Horvath, R., Wanschitz, J., Kiechl, S., Kaguni, L. S., Suomalainen, A. <strong>Functional defects due to spacer-region mutations of human mitochondrial DNA polymerase in a family with an ataxia-myopathy syndrome.</strong> Hum. Molec. Genet. 14: 1907-1920, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15917273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15917273</a>] [<a href="https://doi.org/10.1093/hmg/ddi196" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15917273">Luoma et al. (2005)</a> identified a family segregating 3 POLG amino acid variants: A467T (<a href="#0002">174763.0002</a>), R627Q, and Q1236H. The first 2 affect the spacer region, and the third is a polymorphism, allelic with R627Q. Three grades of disease severity appeared to correlate with the genotypes. The patient with the most severe outcome, cerebellar ataxia syndrome, had all 3 variants; those with R627Q and Q1236H had juvenile-onset ptosis and gait disturbance; those with a single A467T allele had late-onset ptosis. Biochemical analysis of expressed mutant proteins revealed that the A467T substitution resulted in decreased activity, DNA binding, and processivity of the polymerase. Other pathogenic spacer mutants showed DNA-binding affinities and processivities similar to or higher than the controls, suggesting that the disease-causing mechanisms of spacer mutations may extend beyond the basic catalytic functions of POLG. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15917273" 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="#51" class="mim-tip-reference" title="Stewart, J. D., Tennant, S., Powell, H., Pyle, A., Blakely, E. L., He, L., Hudson, G., Roberts, M., du Plessis, D., Gow, D., Mewasingh, L. D., Hanna, M. G., Omer, S., Morris, A. A., Roxburgh, R., Livingston, J. H., McFarland, R., Turnbull, D. M., Chinnery, P. F., Taylor, R. W. <strong>Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children.</strong> J. Med. Genet. 46: 209-214, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19251978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19251978</a>] [<a href="https://doi.org/10.1136/jmg.2008.058180" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19251978">Stewart et al. (2009)</a> identified 27 POLG mutations in 14 probands with a variety of phenotypes, including PEO, Alpers syndrome, and ataxia. All 6 patients with Alpers syndrome carried at least 1 mutation in the linker region of the protein (A467T, or W748S; <a href="#0013">174763.0013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19251978" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of the cellular phenotype derived from 24 children with biallelic POLG1 mutations, 21 of whom had a clinical diagnosis of mitochondrial DNA depletion syndrome-4A, manifest as Alpers syndrome, <a href="#1" class="mim-tip-reference" title="Ashley, N., O'Rourke, A., Smith, C., Adams, S., Gowda, V., Zeviani, M., Brown, G. K., Fratter, C., Poulton, J. <strong>Depletion of mitochondrial DNA in fibroblast cultures from patients with POLG1 mutations is a consequence of catalytic mutations.</strong> Hum. Molec. Genet. 17: 2496-2506, 2008. Note: Erratum: Hum. Molec. Genet. 18: 4905-4906, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18487244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18487244</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18487244[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/ddn150" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18487244">Ashley et al. (2008)</a> found that the cellular mtDNA content reflected the genotype. Those with mtDNA depletion in the liver and/or muscle had at least 1 missense or nonsense mutation in a catalytic domain, either the polymerase or exonuclease region. Four of 12 patients further analyzed showed a progressive, mosaic pattern of mtDNA depletion in fibroblasts, and all had biallelic mutations in catalytic domains. These patients had a severe clinical phenotype with early onset before 1 year of age, hepatic involvement, and death by 16 months of age. Their cells showed respiratory chain defects. Patients with 2 mutations in the linker region of the gene did not show mtDNA depletion and had the mildest phenotype with onset in childhood or adolescence and little liver involvement. The study also found that the average mtDNA content declined with serial passage in cell culture in patients with mtDNA depletion, which <a href="#1" class="mim-tip-reference" title="Ashley, N., O'Rourke, A., Smith, C., Adams, S., Gowda, V., Zeviani, M., Brown, G. K., Fratter, C., Poulton, J. <strong>Depletion of mitochondrial DNA in fibroblast cultures from patients with POLG1 mutations is a consequence of catalytic mutations.</strong> Hum. Molec. Genet. 17: 2496-2506, 2008. Note: Erratum: Hum. Molec. Genet. 18: 4905-4906, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18487244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18487244</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18487244[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/ddn150" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18487244">Ashley et al. (2008)</a> postulated was a result of mtDNA replication stalling, indicating the requirement for both catalytic actions of POLG1 in mitochondrial replication. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18487244" 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="#50" class="mim-tip-reference" title="Sohl, C. D., Kasiviswanathan, R., Copeland, W. C., Anderson, K. S. <strong>Mutations in human DNA polymerase gamma confer unique mechanisms of catalytic deficiency that mirror the disease severity in mitochondrial disorder patients.</strong> Hum. Molec. Genet. 22: 1074-1085, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23208208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23208208</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23208208[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/dds509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23208208">Sohl et al. (2013)</a> performed functional studies of 4 different missense mutations in the POLG gene that are associated with variable phenotypic severity ranging from death in infancy from Alpers syndrome to mild PEO. The mutations from most to least severe were A957P, R1096C, R1096H, and A957S (<a href="#0014">174763.0014</a>); all mutations occurred in the polymerase domain of the catalytic subunit. The mutations did not strongly affect the affinity for the DNA substrate. However, in functional studies, the A957P mutant showed the most striking deficiencies in the incorporation of a correct dNTP compared to wildtype, the R1096C and R1096H showed variable but intermediate defects, and the A957S mutant showed only a small decrease in efficiency, which matched the disease severity associated with the mutations. In addition, the A957P mutant had a 2-fold order of magnitude loss of fidelity compared to wildtype, suggesting that a buildup of mitochondrial mutations may contribute to death in infancy in those with this mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23208208" 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="#13" class="mim-tip-reference" title="Hakonen, A. H., Davidzon, G., Salemi, R., Bindoff, L. A., Van Goethem, G., DiMauro, S., Thorburn, D. R., Suomalainen, A. <strong>Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders.</strong> Europ. J. Hum. Genet. 15: 779-783, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17426723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17426723</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201831" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17426723">Hakonen et al. (2007)</a> demonstrated that the A467T disease chromosomes of patients from Australia, New Zealand, and the United States shared a common haplotype with European patients, indicating that they all derived from a common European founder. The Norwegian A467T disease haplotype diverged from the European founder earlier than the other haplotypes. <a href="#13" class="mim-tip-reference" title="Hakonen, A. H., Davidzon, G., Salemi, R., Bindoff, L. A., Van Goethem, G., DiMauro, S., Thorburn, D. R., Suomalainen, A. <strong>Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders.</strong> Europ. J. Hum. Genet. 15: 779-783, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17426723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17426723</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201831" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17426723">Hakonen et al. (2007)</a> estimated that the common ancestor for A467T lived more than 15 to 30 generations ago, before 1700 to 1400 A.D. Similarly, the disease W748S haplotype in patients from Australia and New Zealand derived from a common European haplotype. This haplotype shared a long region with the Finnish and Norwegian haplotype but differed from Belgian and British patients, suggesting that the W748S founder who formed the isolate in Australia and New Zealand may have been of Scandinavian rather than British origin. The common ancestor for the W748S haplotype lived more than 40 to 60 generations ago, before 1200 to 800 A.D. There was also evidence of a common founder, possibly of European origin, for the G848S (<a href="#0006">174763.0006</a>) mutation. The findings suggested that these mutations did not result from recurrent mutation events but were rather caused by spreading of single founder mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17426723" 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="#55" class="mim-tip-reference" title="Trifunovic, A., Wredenberg, A., Falkenberg, M., Spelbrink, J. N., Rovio, A. T., Bruder, C. E., Bohlooly-Y, M., Gidlof, S., Oldfors, A., Wibom, R., Tornell, J., Jacobs, H. T., Larsson, N.-G. <strong>Premature ageing in mice expressing defective mitochondrial DNA polymerase.</strong> Nature 429: 417-423, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15164064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15164064</a>] [<a href="https://doi.org/10.1038/nature02517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15164064">Trifunovic et al. (2004)</a> created homozygous knockin mice that expressed a proofreading-deficient version of PolgA, the nucleus-encoded catalytic subunit of mtDNA polymerase. The knockin mice developed an mtDNA mutator phenotype with a 3- to 5-fold increase in the levels of point mutations, as well as increased amounts of deleted mtDNA. This increase in somatic mtDNA mutations is associated with reduced life span and premature onset of aging-related phenotypes such as weight loss, reduced subcutaneous fat, alopecia, kyphosis, osteoporosis, anemia, reduced fertility, and heart enlargement. <a href="#55" class="mim-tip-reference" title="Trifunovic, A., Wredenberg, A., Falkenberg, M., Spelbrink, J. N., Rovio, A. T., Bruder, C. E., Bohlooly-Y, M., Gidlof, S., Oldfors, A., Wibom, R., Tornell, J., Jacobs, H. T., Larsson, N.-G. <strong>Premature ageing in mice expressing defective mitochondrial DNA polymerase.</strong> Nature 429: 417-423, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15164064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15164064</a>] [<a href="https://doi.org/10.1038/nature02517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15164064">Trifunovic et al. (2004)</a> concluded that their results provided a causative link between mtDNA mutations and aging phenotypes in mammals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15164064" 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="#21" class="mim-tip-reference" title="Kujoth, G. C., Hiona, A., Pugh, T. D., Someya, S., Panzer, K., Wohlgemuth, S. E., Hofer, T., Seo, A. Y., Sullivan, R., Jobling, W. A., Morrow, J. D., Van Remmen, H., Sedivy, J. M., Yamasoba, T., Tanokura, M., Weindruch, R., Leeuwenburgh, C., Prolla, T. A. <strong>Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging.</strong> Science 309: 481-484, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16020738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16020738</a>] [<a href="https://doi.org/10.1126/science.1112125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16020738">Kujoth et al. (2005)</a> demonstrated that the mice generated by <a href="#55" class="mim-tip-reference" title="Trifunovic, A., Wredenberg, A., Falkenberg, M., Spelbrink, J. N., Rovio, A. T., Bruder, C. E., Bohlooly-Y, M., Gidlof, S., Oldfors, A., Wibom, R., Tornell, J., Jacobs, H. T., Larsson, N.-G. <strong>Premature ageing in mice expressing defective mitochondrial DNA polymerase.</strong> Nature 429: 417-423, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15164064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15164064</a>] [<a href="https://doi.org/10.1038/nature02517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15164064">Trifunovic et al. (2004)</a> (D257A mice) accumulated mtDNA mutations and display features of accelerated aging. Accumulation of mtDNA mutations was not associated with increased markers of oxidative stress or a defect in cellular proliferation, but was correlated with the induction of apoptotic markers, particularly in tissues characterized by rapid cell turnover. The levels of apoptotic markers were also found to increase during aging in normal mice. <a href="#21" class="mim-tip-reference" title="Kujoth, G. C., Hiona, A., Pugh, T. D., Someya, S., Panzer, K., Wohlgemuth, S. E., Hofer, T., Seo, A. Y., Sullivan, R., Jobling, W. A., Morrow, J. D., Van Remmen, H., Sedivy, J. M., Yamasoba, T., Tanokura, M., Weindruch, R., Leeuwenburgh, C., Prolla, T. A. <strong>Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging.</strong> Science 309: 481-484, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16020738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16020738</a>] [<a href="https://doi.org/10.1126/science.1112125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16020738">Kujoth et al. (2005)</a> concluded that accumulation of mtDNA mutations that promote apoptosis may be a central mechanism driving mammalian aging. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16020738+15164064" 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="#35" class="mim-tip-reference" title="Miller, R. A. <strong>Evaluating evidence for aging. (Letter)</strong> Science 310: 441 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16239461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16239461</a>] [<a href="https://doi.org/10.1126/science.310.5747.441" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16239461">Miller (2005)</a> and <a href="#10" class="mim-tip-reference" title="Gershon, D. <strong>Evaluating evidence for aging. (Letter)</strong> Science 310: 441 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16245397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16245397</a>]" pmid="16245397">Gershon (2005)</a> questioned whether the phenotype of aging described by <a href="#21" class="mim-tip-reference" title="Kujoth, G. C., Hiona, A., Pugh, T. D., Someya, S., Panzer, K., Wohlgemuth, S. E., Hofer, T., Seo, A. Y., Sullivan, R., Jobling, W. A., Morrow, J. D., Van Remmen, H., Sedivy, J. M., Yamasoba, T., Tanokura, M., Weindruch, R., Leeuwenburgh, C., Prolla, T. A. <strong>Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging.</strong> Science 309: 481-484, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16020738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16020738</a>] [<a href="https://doi.org/10.1126/science.1112125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16020738">Kujoth et al. (2005)</a> was really an accelerated aging phenotype. Some of the mice exhibited severe anemia and loss of intestinal crypt cells not commonly seen in aged mice. <a href="#40" class="mim-tip-reference" title="Prolla, T. A., Weindruch, R. H. <strong>Response: Evaluating evidence for aging. (Letter)</strong> Science 310: 441-442, 2005."None>Prolla and Weindruch (2005)</a> commented that hearing loss and sarcopenia as seen in the D257A mice are commonly observed in aging and that the more severe phenotype such as anemia and loss of intestinal crypts are likely to be secondary to complete stem cell depletion, which is not observed in normal aging. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16020738+16239461+16245397" 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="Hance, N., Ekstrand, M. I., Trifunovic, A. <strong>Mitochondrial DNA polymerase gamma is essential for mammalian embryogenesis.</strong> Hum. Molec. Genet. 14: 1775-1783, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15888483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15888483</a>] [<a href="https://doi.org/10.1093/hmg/ddi184" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15888483">Hance et al. (2005)</a> demonstrated that PolgA deficiency in mouse embryos caused an early developmental arrest between embryonic days 7.5 and 8.5 associated with severe mtDNA depletion. PolgA +/- mice had half the wildtype levels of PolgA transcripts and a slight reduction in mtDNA levels, but developed normally. PolgA transcripts in PolgA +/- mice increased in response to artificially elevated mtDNA copy number, revealing a possible regulatory link between mtDNA maintenance and PolgA expression. <a href="#15" class="mim-tip-reference" title="Hance, N., Ekstrand, M. I., Trifunovic, A. <strong>Mitochondrial DNA polymerase gamma is essential for mammalian embryogenesis.</strong> Hum. Molec. Genet. 14: 1775-1783, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15888483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15888483</a>] [<a href="https://doi.org/10.1093/hmg/ddi184" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15888483">Hance et al. (2005)</a> concluded that Polg indeed is the only DNA polymerase capable of maintaining mtDNA in mammalian mitochondria, and appears to be essential for the organogenesis during mammalian embryonic development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15888483" 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="#63" class="mim-tip-reference" title="Vermulst, M., Wanagat, J., Kujoth, G. C., Bielas, J. H., Rabinovitch, P. S., Prolla, T. A., Loeb, L. A. <strong>DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice.</strong> Nature Genet. 40: 392-394, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18311139/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18311139</a>] [<a href="https://doi.org/10.1038/ng.95" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18311139">Vermulst et al. (2008)</a> identified mitochondrial DNA deletions as a driving force behind the premature aging phenotype of the mitochondrial mutator mice developed by <a href="#55" class="mim-tip-reference" title="Trifunovic, A., Wredenberg, A., Falkenberg, M., Spelbrink, J. N., Rovio, A. T., Bruder, C. E., Bohlooly-Y, M., Gidlof, S., Oldfors, A., Wibom, R., Tornell, J., Jacobs, H. T., Larsson, N.-G. <strong>Premature ageing in mice expressing defective mitochondrial DNA polymerase.</strong> Nature 429: 417-423, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15164064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15164064</a>] [<a href="https://doi.org/10.1038/nature02517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15164064">Trifunovic et al. (2004)</a>. <a href="#63" class="mim-tip-reference" title="Vermulst, M., Wanagat, J., Kujoth, G. C., Bielas, J. H., Rabinovitch, P. S., Prolla, T. A., Loeb, L. A. <strong>DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice.</strong> Nature Genet. 40: 392-394, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18311139/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18311139</a>] [<a href="https://doi.org/10.1038/ng.95" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18311139">Vermulst et al. (2008)</a> provided evidence for homology-directed DNA repair mechanism in mitochondria that is directly linked to the formation of mitochondrial DNA deletions. In addition, their results demonstrated that the rate at which mitochondrial DNA mutations reach phenotypic expression differs markedly among tissues, which may be an important factor in determining the tolerance of a tissue to random mitochondrial mutagenesis. Mitochondrial mutator mice showed a 7- to 11-fold increase in mitochondrial DNA deletions over those in wildtype mice or mice heterozygous for this PolgA mutation. <a href="#63" class="mim-tip-reference" title="Vermulst, M., Wanagat, J., Kujoth, G. C., Bielas, J. H., Rabinovitch, P. S., Prolla, T. A., Loeb, L. A. <strong>DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice.</strong> Nature Genet. 40: 392-394, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18311139/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18311139</a>] [<a href="https://doi.org/10.1038/ng.95" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18311139">Vermulst et al. (2008)</a> found that duodenum, heart, and brain tissue from prematurely aging PolgA homozygous mutator mice contained many COX-negative cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15164064+18311139" 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>Using a series of mouse mutants to investigate the extent to which inherited mtDNA mutations can contribute to aging, <a href="#44" class="mim-tip-reference" title="Ross, J. M., Stewart, J. B., Hagstrom, E., Brene, S., Mourier, A., Coppotelli, G., Freyer, C., Lagouge, M., Hoffer, B. J., Olson, L., Larsson, N.-G. <strong>Germline mitochondrial DNA mutations aggravate ageing and can impair brain development.</strong> Nature 501: 412-415, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23965628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23965628</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23965628[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/10.1038/nature12474" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23965628">Ross et al. (2013)</a> found that maternally transmitted mtDNA mutations can induce mild aging phenotypes in mice with a wildtype nuclear genome. Maternally transmitted mtDNA mutations led to anticipation of reduced fertility in mice that were heterozygous for the mtDNA mutator allele (PolgA-wt/mut) and aggravated premature aging phenotypes in mtDNA mutator mice (PolgA-mut/mut). Unexpectedly, a combination of maternally transmitted and somatic mtDNA mutations also led to stochastic brain malformations. <a href="#44" class="mim-tip-reference" title="Ross, J. M., Stewart, J. B., Hagstrom, E., Brene, S., Mourier, A., Coppotelli, G., Freyer, C., Lagouge, M., Hoffer, B. J., Olson, L., Larsson, N.-G. <strong>Germline mitochondrial DNA mutations aggravate ageing and can impair brain development.</strong> Nature 501: 412-415, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23965628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23965628</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23965628[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/10.1038/nature12474" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23965628">Ross et al. (2013)</a> concluded that a preexisting mutation load will not only allow somatic mutagenesis to create a critically high total mtDNA mutation load sooner but will also increase clonal expansion mtDNA mutations to enhance the normally occurring mosaic respiratory chain deficiency in aging tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23965628" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Kang, Y., Hepojoki, J., Maldonado, R. S., Mito, T., Terzioglu, M., Manninen, T., Kant, R., Singh, S., Othman, A., Verma, R., Uusimaa, J., Wartiovaara, K., Kareinen, L., Zamboni, N., Nyman, T. A., Paetau, A., Kipar, A., Vapalahti, O., Suomalainen, A. <strong>Ancestral allele of DNA polymerase gamma modifies antiviral tolerance.</strong> Nature 628: 844-853, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38570685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38570685</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=38570685[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/10.1038/s41586-024-07260-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38570685">Kang et al. (2024)</a> generated mutant mice homozygous for an allele with 2 mutations in the Polg1 gene, W726S+E1121G, corresponding to the human POLG1 allele with W748S and E1143G (see <a href="#0013">174763.0013</a>). The mutant mice had decreased treadmill performance as well as decreased mitochondrial content in various tissues and decreased mtDNA content in the liver. Mice that were infected with tick-born encephalitis virus (TBEV) demonstrated decreased interferon-1 (see <a href="/entry/147660">147660</a>) pathway signaling and increased proinflammatory signaling compared to controls. Following infection, the mutant mice developed abnormal depletion of nucleotide and mtDNA pools, which are known to be necessary in viral replication. Brains of infected mice demonstrated reduction of GABAergic neurons. Livers of infected mutant mice were inflamed, with increased expression of the necroptosis marker phosphorylated MLKL (<a href="/entry/615153">615153</a>) and decreased POLG1 expression. Furthermore, elevated levels of IL6 (<a href="/entry/147620">147620</a>) were detected in mutant mouse serum. <a href="#18" class="mim-tip-reference" title="Kang, Y., Hepojoki, J., Maldonado, R. S., Mito, T., Terzioglu, M., Manninen, T., Kant, R., Singh, S., Othman, A., Verma, R., Uusimaa, J., Wartiovaara, K., Kareinen, L., Zamboni, N., Nyman, T. A., Paetau, A., Kipar, A., Vapalahti, O., Suomalainen, A. <strong>Ancestral allele of DNA polymerase gamma modifies antiviral tolerance.</strong> Nature 628: 844-853, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38570685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38570685</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=38570685[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/10.1038/s41586-024-07260-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38570685">Kang et al. (2024)</a> concluded that the mutant Polg1 allele resulted in an aberrant innate immune response to viral infection, resulting in depletion of GABAergic neurons and liver necrosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38570685" 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>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=174763[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 1</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">rs113994099 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994099;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=rs113994099" 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=rs113994099" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a 3-generation Belgian pedigree with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions (PEOA1; <a href="/entry/157640">157640</a>), <a href="#57" class="mim-tip-reference" title="Van Goethem, G., Dermaut, B., Lofgren, A., Martin, J.-J., Van Broeckhoven, C. <strong>Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions.</strong> Nature Genet. 28: 211-212, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431686/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431686</a>] [<a href="https://doi.org/10.1038/90034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431686">Van Goethem et al. (2001)</a> identified a 2864A-G transition in the POLG gene, resulting in a tyr955-to-cys (Y955C) substitution in the polymerase B domain of the protein. The tyrosine at codon 955 is highly conserved. Segregation analysis showed complete cosegregation of Y955C with autosomal dominant PEO (maximum lod = 4.01 at theta = 0.0). The mutation was present in the 8 patients and 2 of 15 at-risk individuals; it was absent in 432 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11431686" 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="#23" class="mim-tip-reference" title="Lamantea, E., Tiranti, V., Bordoni, A., Toscano, A., Bono, F., Servidei, S., Papadimitriou, A., Spelbrink, H., Silvestri, L., Casari, G., Comi, G. P., Zeviani, M. <strong>Mutations of mitochondrial DNA polymerase gamma-A are a frequent cause of autosomal dominant or recessive progressive external ophthalmoplegia.</strong> Ann. Neurol. 52: 211-219, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12210792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12210792</a>] [<a href="https://doi.org/10.1002/ana.10278" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12210792">Lamantea et al. (2002)</a> identified the heterozygous Y955C mutation in 5 unrelated families with adPEO. Four families were Italian and 1 was from Greece; 1 of the Italian families was originally reported by <a href="#67" class="mim-tip-reference" title="Zeviani, M., Servidei, S., Gellera, C., Bertini, E., DiMauro, S., DiDonato, S. <strong>An autosomal dominant disorder with multiple deletions of mitochondrial DNA starting at the D-loop region.</strong> Nature 339: 309-311, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2725645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2725645</a>] [<a href="https://doi.org/10.1038/339309a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2725645">Zeviani et al. (1989)</a> and <a href="#48" class="mim-tip-reference" title="Servidei, S., Zeviani, M., Manfredi, G., Ricci, E., Silvestri, G., Bertini, E., Gellera, C., DiMauro, S., DiDonato, S., Tonali, P. <strong>Dominantly inherited mitochondrial myopathy with multiple deletions of mitochondrial DNA: clinical, morphologic and biochemical studies.</strong> Neurology 41: 1053-1059, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2067633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2067633</a>] [<a href="https://doi.org/10.1212/wnl.41.7.1053" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2067633">Servidei et al. (1991)</a>. Microsatellite analysis did not identify a common disease haplotype in these families. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12210792+2067633+2725645" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To analyze the effects of the Y955C mutation on the kinetics and fidelity of DNA synthesis, <a href="#39" class="mim-tip-reference" title="Ponamarev, M. V., Longley, M. J., Nguyen, D., Kunkel, T. A., Copeland, W. C. <strong>Active site mutation in DNA polymerase-gamma associated with progressive external ophthalmoplegia causes error-prone DNA synthesis.</strong> J. Biol. Chem. 277: 15225-15228, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11897778/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11897778</a>] [<a href="https://doi.org/10.1074/jbc.C200100200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11897778">Ponamarev et al. (2002)</a> expressed the Y955C mutant protein in Sf9 cells by site-directed mutagenesis. The Y955C enzyme retained a wildtype catalytic rate and demonstrated a 45-fold decrease in apparent binding affinity for the incoming nucleoside triphosphate, but the authors noted that mitochondrial matrix pools are usually high enough to overcome this reduced affinity. Fidelity studies showed that the Y955C derivative was 2-fold less accurate for basepair substitutions than wildtype, even with proofreading activity. Genetic inactivation of the exonuclease revealed a 10- to 100-fold increase in mismatch errors. <a href="#39" class="mim-tip-reference" title="Ponamarev, M. V., Longley, M. J., Nguyen, D., Kunkel, T. A., Copeland, W. C. <strong>Active site mutation in DNA polymerase-gamma associated with progressive external ophthalmoplegia causes error-prone DNA synthesis.</strong> J. Biol. Chem. 277: 15225-15228, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11897778/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11897778</a>] [<a href="https://doi.org/10.1074/jbc.C200100200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11897778">Ponamarev et al. (2002)</a> presented a model in which the enhanced error rate of the mutant enzyme promotes mtDNA deletions, as seen in PEO, via a slippage mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11897778" 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 affected members of 4 adPEO families, including the Swedish family originally reported by <a href="#28" class="mim-tip-reference" title="Lundberg, P. O. <strong>Ocular myopathy with hypogonadism.</strong> Acta Neurol. Scand. 38: 142-155, 1962.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14467368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14467368</a>] [<a href="https://doi.org/10.1111/j.1600-0404.1962.tb01084.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14467368">Lundberg (1962)</a>, <a href="#29" class="mim-tip-reference" title="Luoma, P., Melberg, A., Rinne, J. O., Kaukonen, J. A., Nupponen, N. N., Chalmers, R. M., Oldfors, A., Rautakorpi, I., Peltonen, L., Majamaa, K., Somer, H., Suomalainen, A. <strong>Parkinsonism, premature menopause, and mitochondrial DNA polymerase-gamma mutations: clinical and molecular genetic study.</strong> Lancet 364: 875-882, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15351195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15351195</a>] [<a href="https://doi.org/10.1016/S0140-6736(04)16983-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15351195">Luoma et al. (2004)</a> identified the heterozygous Y955C mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15351195+14467368" 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 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE 1</strong>
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SENSORY ATAXIC NEUROPATHY, DYSARTHRIA, AND OPHTHALMOPARESIS, INCLUDED<br />
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SPINOCEREBELLAR ATAXIA WITH EPILEPSY, INCLUDED<br />
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MITOCHONDRIAL DNA DEPLETION SYNDROME 4A (ALPERS TYPE), INCLUDED
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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> rs113994095 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994095;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/rs113994095?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=rs113994095" 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=rs113994095" 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=RCV000014440 OR RCV000014441 OR RCV000014442 OR RCV000014443 OR RCV000184011 OR RCV000188658 OR RCV000347876 OR RCV000508942 OR RCV001004604 OR RCV001095683 OR RCV001198082 OR RCV001376079 OR RCV001731286 OR RCV001813983 OR RCV001847600 OR RCV002273931 OR RCV002316195" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014440, RCV000014441, RCV000014442, RCV000014443, RCV000184011, RCV000188658, RCV000347876, RCV000508942, RCV001004604, RCV001095683, RCV001198082, RCV001376079, RCV001731286, RCV001813983, RCV001847600, RCV002273931, RCV002316195" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014440...</a>
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<p>In a family with 3 affected sibs with autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletion (PEOB1; <a href="/entry/258450">258450</a>), <a href="#57" class="mim-tip-reference" title="Van Goethem, G., Dermaut, B., Lofgren, A., Martin, J.-J., Van Broeckhoven, C. <strong>Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions.</strong> Nature Genet. 28: 211-212, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431686/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431686</a>] [<a href="https://doi.org/10.1038/90034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431686">Van Goethem et al. (2001)</a> identified compound heterozygosity for 2 missense mutations in the POLG gene: a 1399G-A transition, resulting in an ala467-to-thr (A467T) substitution, and a 911T-G transversion, resulting in a leu304-to-arg substitution (L304R; <a href="#0003">174763.0003</a>). In 2 affected individuals in another family, <a href="#57" class="mim-tip-reference" title="Van Goethem, G., Dermaut, B., Lofgren, A., Martin, J.-J., Van Broeckhoven, C. <strong>Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions.</strong> Nature Genet. 28: 211-212, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431686/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431686</a>] [<a href="https://doi.org/10.1038/90034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431686">Van Goethem et al. (2001)</a> identified the A467T mutation in compound heterozygous state with an 8G-C transversion, resulting in an arg3-to-pro substitution (R3P; <a href="#0004">174763.0004</a>). Three of 229 control individuals were heterozygous for A467T (allele T frequency of 0.6%). The R3P mutation was not observed in any of the control individuals. The A467T mutation occurs in the linker region of the protein (<a href="#51" class="mim-tip-reference" title="Stewart, J. D., Tennant, S., Powell, H., Pyle, A., Blakely, E. L., He, L., Hudson, G., Roberts, M., du Plessis, D., Gow, D., Mewasingh, L. D., Hanna, M. G., Omer, S., Morris, A. A., Roxburgh, R., Livingston, J. H., McFarland, R., Turnbull, D. M., Chinnery, P. F., Taylor, R. W. <strong>Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children.</strong> J. Med. Genet. 46: 209-214, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19251978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19251978</a>] [<a href="https://doi.org/10.1136/jmg.2008.058180" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19251978">Stewart et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19251978+11431686" 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="#60" class="mim-tip-reference" title="Van Goethem, G., Martin, J. J., Dermaut, B., Lofgren, A., Wibail, A., Ververken, D., Tack, P., Dehaene, I., Van Zandijcke, M., Moonen, M., Ceuterick, C., De Jonghe, P., Van Broeckhoven, C. <strong>Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia.</strong> Neuromusc. Disord. 13: 133-142, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12565911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12565911</a>] [<a href="https://doi.org/10.1016/s0960-8966(02)00216-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12565911">Van Goethem et al. (2003)</a> stated that the A467T mutation has a frequency of 0.6% in the Belgian population and that sensory neuropathy is the initial feature in Belgian compound heterozygous autosomal recessive progressive external ophthalmoplegia patients, all carrying the POLG A467T mutation in combination with another mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12565911" 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="#61" class="mim-tip-reference" title="Van Goethem, G., Mercelis, R., Lofgren, A., Seneca, S., Ceuterick, C., Martin, J. J., Van Broeckhoven, C. <strong>Patient homozygous for a recessive POLG mutation presents with features of MERRF.</strong> Neurology 61: 1811-1813, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14694057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14694057</a>] [<a href="https://doi.org/10.1212/01.wnl.0000098997.23471.65" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14694057">Van Goethem et al. (2003)</a> reported a patient who was homozygous for the A467T mutation, which they incorrectly reported as ALA476THR. (<a href="#56" class="mim-tip-reference" title="Van Broeckhoven, C. <strong>Personal Communication.</strong> Antwerp, Belgium 2/9/2004."None>Van Broeckhoven (2004)</a> reported the correct mutation as A467T.) At age 15 years, the patient experienced mild ataxia, and later developed myoclonus, seizures, and sensory neuropathy. External ophthalmoplegia was absent on repeated examinations. Muscle biopsy did not show any abnormalities, including no ragged-red fibers, but long-range PCR detected a low proportion of mtDNA deletions in the patient's muscle. <a href="#61" class="mim-tip-reference" title="Van Goethem, G., Mercelis, R., Lofgren, A., Seneca, S., Ceuterick, C., Martin, J. J., Van Broeckhoven, C. <strong>Patient homozygous for a recessive POLG mutation presents with features of MERRF.</strong> Neurology 61: 1811-1813, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14694057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14694057</a>] [<a href="https://doi.org/10.1212/01.wnl.0000098997.23471.65" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14694057">Van Goethem et al. (2003)</a> noted that the clinical features in this patient were unique and suggested that some features overlapped with the syndrome of myoclonus, epilepsy, and ragged-red fibers (MERRF; <a href="/entry/545000">545000</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14694057" 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 sibs with sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO; <a href="/entry/607459">607459</a>), originally reported by <a href="#41" class="mim-tip-reference" title="Rantamaki, M., Krahe, R., Paetau, A., Cormand, B., Mononen, I., Udd, B. <strong>Adult-onset autosomal recessive ataxia with thalamic lesions in a Finnish family.</strong> Neurology 57: 1043-1049, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11571332/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11571332</a>] [<a href="https://doi.org/10.1212/wnl.57.6.1043" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11571332">Rantamaki et al. (2001)</a>, <a href="#59" class="mim-tip-reference" title="Van Goethem, G., Luoma, P., Rantamaki, M., Al Memar, A., Kaakkola, S., Hackman, P., Krahe, R., Lofgren, A., Martin, J. J., De Jonghe, P., Suomalainen, A., Udd, B., Van Broeckhoven, C. <strong>POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement.</strong> Neurology 63: 1251-1257, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15477547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15477547</a>] [<a href="https://doi.org/10.1212/01.wnl.0000140494.58732.83" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15477547">Van Goethem et al. (2004)</a> identified homozygosity for the A467T mutation. An unrelated British patient was compound heterozygous for the A467T mutation and W748S (<a href="#0013">174763.0013</a>). An unrelated Belgian patient with a variant form of SANDO without ophthalmoparesis was also homozygous for the A467T mutation. That patient had psychiatric symptoms, severe gastroparesis, and dilated cardiomyopathy, illustrating the variable clinical phenotype that can result from recessive POLG mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11571332+15477547" 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 2 affected patients from a family with mitochondrial DNA depletion syndrome-4A (MTDPS4A; <a href="/entry/203700">203700</a>), manifest as Alpers syndrome, <a href="#37" class="mim-tip-reference" title="Naviaux, R. K., Nguyen, K. V. <strong>POLG mutations associated with Alpers syndrome and mitochondrial DNA depletion. (Letter)</strong> Ann. Neurol. 58: 491 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16130100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16130100</a>] [<a href="https://doi.org/10.1002/ana.20544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16130100">Naviaux and Nguyen (2005)</a> identified compound heterozygosity for 2 mutations in the POLG gene: A467T and E873X (<a href="#0008">174763.0008</a>). An earlier report on these patients by <a href="#36" class="mim-tip-reference" title="Naviaux, R. K., Nguyen, K. V. <strong>POLG mutations associated with Alpers' syndrome and mitochondrial DNA depletion.</strong> Ann. Neurol. 55: 706-712, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15122711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15122711</a>] [<a href="https://doi.org/10.1002/ana.20079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15122711">Naviaux and Nguyen (2004)</a> had incorrectly stated that they were homozygous for the E873X mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16130100+15122711" 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 2 sisters with mtDNA depletion syndrome manifest as Alpers syndrome, <a href="#38" class="mim-tip-reference" title="Nguyen, K. V., Ostergaard, E., Ravn, S. H., Balslev, T., Danielsen, E. R., Vardag, A., McKiernan, P. J., Gray, G., Naviaux, R. K. <strong>POLG mutations in Alpers syndrome.</strong> Neurology 65: 1493-1495, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16177225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16177225</a>] [<a href="https://doi.org/10.1212/01.wnl.0000182814.55361.70" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16177225">Nguyen et al. (2005)</a> identified compound heterozygosity for 2 mutations in the POLG gene: a A467T and W1020X (<a href="#0017">174763.0017</a>). Two affected sibs from another family with Alpers syndrome were compound heterozygous for A467T and G848S (<a href="#0006">174763.0006</a>). Another child with Alpers syndrome from an unrelated family who was homozygous for the A467T mutation showed late-onset at age 8.5 years and death by age 9 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16177225" 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="#66" class="mim-tip-reference" title="Winterthun, S., Ferrari, G., He, L., Taylor, R. W., Zeviani, M., Turnbull, D. M., Engelsen, B. A., Moen, G., Bindoff, L. A. <strong>Autosomal recessive mitochondrial ataxic syndrome due to mitochondrial polymerase-gamma mutations.</strong> Neurology 64: 1204-1208, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15824347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15824347</a>] [<a href="https://doi.org/10.1212/01.WNL.0000156516.77696.5A" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15824347">Winterthun et al. (2005)</a> identified homozygosity for the A467T mutation in affected members from 2 families with a form of SANDO characterized by early onset of migraine headaches and/or seizures, and the later development of myoclonus (see SCAE; <a href="/entry/607459">607459</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15824347" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Hakonen, A. H., Davidzon, G., Salemi, R., Bindoff, L. A., Van Goethem, G., DiMauro, S., Thorburn, D. R., Suomalainen, A. <strong>Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders.</strong> Europ. J. Hum. Genet. 15: 779-783, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17426723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17426723</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201831" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17426723">Hakonen et al. (2007)</a> demonstrated that the A467T disease chromosomes of patients from Australia, New Zealand, and the United States shared a common haplotype with European patients, indicating that they all derived from a common European founder. Further analysis indicated that the Norwegian A467T disease haplotype diverged from the European founder earlier than the other haplotypes. <a href="#13" class="mim-tip-reference" title="Hakonen, A. H., Davidzon, G., Salemi, R., Bindoff, L. A., Van Goethem, G., DiMauro, S., Thorburn, D. R., Suomalainen, A. <strong>Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders.</strong> Europ. J. Hum. Genet. 15: 779-783, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17426723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17426723</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201831" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17426723">Hakonen et al. (2007)</a> estimated that the common ancestor for A467T lived more than 15 to 30 generations ago, before 1700 to 1400 A.D. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17426723" 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 reevaluation of 2 sibs reported by <a href="#3" class="mim-tip-reference" title="Bird, T. D., Shaw, C. M. <strong>Progressive myoclonus and epilepsy with dentatorubral degeneration: a clinicopathological study of the Ramsay Hunt syndrome.</strong> J. Neurol. Neurosurg. Psychiat. 41: 140-149, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/632821/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">632821</a>] [<a href="https://doi.org/10.1136/jnnp.41.2.140" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="632821">Bird and Shaw (1978)</a>, who were classified as having progressive myoclonic epilepsy-5 (EPM5; see <a href="/entry/607459">607459</a>), <a href="#47" class="mim-tip-reference" title="Sandford, E., Bird, T. D., Li, J. Z., Burmeister, M. <strong>PRICKLE2 mutations might not be involved in epilepsy. (Letter)</strong> Am. J. Hum. Genet. 98: 588-589, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26942291/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26942291</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.01.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26942291">Sandford et al. (2016)</a> identified compound heterozygous mutations in the POLG gene (A467T on 1 allele and W748S, <a href="#0013">174763.0013</a> and G497H, <a href="#0016">174763.0016</a> in cis on the other allele). In these sibs, <a href="#54" class="mim-tip-reference" title="Tao, H., Manak, J. R., Sowers, L., Mei, X., Kiyonari, H., Abe, T., Dahdaleh, N. S., Yang, T., Wu, S., Chen, S., Fox, M. H., Gurnett, C., and 24 others. <strong>Mutations in prickle orthologs cause seizures in flies, mice, and humans.</strong> Am. J. Hum. Genet. 88: 138-149, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21276947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21276947</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21276947[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.2010.12.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21276947">Tao et al. (2011)</a> had previously identified 2 heterozygous missense variants in the PRICKLE2 gene (<a href="/entry/608501#0001">608501.0001</a>) that occurred on the same allele. Furthermore, <a href="#47" class="mim-tip-reference" title="Sandford, E., Bird, T. D., Li, J. Z., Burmeister, M. <strong>PRICKLE2 mutations might not be involved in epilepsy. (Letter)</strong> Am. J. Hum. Genet. 98: 588-589, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26942291/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26942291</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.01.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26942291">Sandford et al. (2016)</a> showed that the 2 heterozygous missense variants in the PRICKLE2 gene identified by <a href="#54" class="mim-tip-reference" title="Tao, H., Manak, J. R., Sowers, L., Mei, X., Kiyonari, H., Abe, T., Dahdaleh, N. S., Yang, T., Wu, S., Chen, S., Fox, M. H., Gurnett, C., and 24 others. <strong>Mutations in prickle orthologs cause seizures in flies, mice, and humans.</strong> Am. J. Hum. Genet. 88: 138-149, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21276947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21276947</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21276947[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.2010.12.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21276947">Tao et al. (2011)</a> occurred on opposite chromosomes, which would be more consistent with recessive inheritance. <a href="#47" class="mim-tip-reference" title="Sandford, E., Bird, T. D., Li, J. Z., Burmeister, M. <strong>PRICKLE2 mutations might not be involved in epilepsy. (Letter)</strong> Am. J. Hum. Genet. 98: 588-589, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26942291/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26942291</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.01.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26942291">Sandford et al. (2016)</a> concluded that the phenotype in these patients resulted from the POLG mutations and not from the PRICKLE2 variants. In a response, <a href="#32" class="mim-tip-reference" title="Mahajan, V. B., Bassuk, A. G. <strong>Response to Sandford et al.: PRICKLE2 variants in epilepsy: a call for precision medicine</strong> Am. J. Hum. Genet. 98: 590-591, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26942292/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26942292</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.02.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26942292">Mahajan and Bassuk (2016)</a> maintained that the PRICKLE2 variants identified by <a href="#54" class="mim-tip-reference" title="Tao, H., Manak, J. R., Sowers, L., Mei, X., Kiyonari, H., Abe, T., Dahdaleh, N. S., Yang, T., Wu, S., Chen, S., Fox, M. H., Gurnett, C., and 24 others. <strong>Mutations in prickle orthologs cause seizures in flies, mice, and humans.</strong> Am. J. Hum. Genet. 88: 138-149, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21276947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21276947</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21276947[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.2010.12.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21276947">Tao et al. (2011)</a> contributed to the phenotype in their patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21276947+26942292+632821+26942291" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE 1</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> rs121918044 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918044;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/rs121918044?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=rs121918044" 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=rs121918044" 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=RCV000014444 OR RCV000188648 OR RCV000626287 OR RCV000762954 OR RCV001266602 OR RCV001813984 OR RCV003387722 OR RCV005007843" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014444, RCV000188648, RCV000626287, RCV000762954, RCV001266602, RCV001813984, RCV003387722, RCV005007843" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014444...</a>
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<p>For discussion of the leu304-to-arg (L304R) mutation in the POLG gene that was found in compound heterozygous state in 3 sibs with autosomal recessive progressive ophthalmoplegia with mitochondrial DNA deletions (PEOB1; <a href="/entry/258450">258450</a>) by <a href="#57" class="mim-tip-reference" title="Van Goethem, G., Dermaut, B., Lofgren, A., Martin, J.-J., Van Broeckhoven, C. <strong>Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions.</strong> Nature Genet. 28: 211-212, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431686/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431686</a>] [<a href="https://doi.org/10.1038/90034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431686">Van Goethem et al. (2001)</a>, see <a href="#0002">174763.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11431686" 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 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE 1</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">rs121918045 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918045;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=rs121918045" 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=rs121918045" 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=RCV000014445" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014445" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014445</a>
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<p>For discussion of the arg3-to-pro (R3P) mutation in the POLG gene that was found in compound heterozygous state in 2 members of a family with autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions (PEOB1; <a href="/entry/258450">258450</a>) by <a href="#57" class="mim-tip-reference" title="Van Goethem, G., Dermaut, B., Lofgren, A., Martin, J.-J., Van Broeckhoven, C. <strong>Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions.</strong> Nature Genet. 28: 211-212, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431686/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431686</a>] [<a href="https://doi.org/10.1038/90034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431686">Van Goethem et al. (2001)</a>, see <a href="#0002">174763.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11431686" 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 SENSORY ATAXIC NEUROPATHY, DYSARTHRIA, AND OPHTHALMOPARESIS</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> rs121918046 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918046;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/rs121918046?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=rs121918046" 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=rs121918046" 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=RCV000014446 OR RCV001382679 OR RCV001781264 OR RCV004579531 OR RCV005003357" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014446, RCV001382679, RCV001781264, RCV004579531, RCV005003357" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014446...</a>
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<p>In a sporadic case of SANDO (<a href="/entry/607459">607459</a>), <a href="#60" class="mim-tip-reference" title="Van Goethem, G., Martin, J. J., Dermaut, B., Lofgren, A., Wibail, A., Ververken, D., Tack, P., Dehaene, I., Van Zandijcke, M., Moonen, M., Ceuterick, C., De Jonghe, P., Van Broeckhoven, C. <strong>Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia.</strong> Neuromusc. Disord. 13: 133-142, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12565911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12565911</a>] [<a href="https://doi.org/10.1016/s0960-8966(02)00216-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12565911">Van Goethem et al. (2003)</a> found compound heterozygosity for 2 mutations in the POLG gene: A467T (<a href="#0002">174763.0002</a>) and arg627-to-trp (R627W). The R627W mutation came from the father, and the A467T mutation from the mother. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12565911" 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 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE 1</strong>
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PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, DIGENIC, INCLUDED<br />
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MITOCHONDRIAL DNA DEPLETION SYNDROME 4A (ALPERS TYPE), INCLUDED<br />
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MITOCHONDRIAL DNA DEPLETION SYNDROME 4B (MNGIE TYPE), INCLUDED
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POLG, GLY848SER
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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> rs113994098 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994098;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/rs113994098?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=rs113994098" 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=rs113994098" 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=RCV000014449 OR RCV000014450 OR RCV000014451 OR RCV000014452 OR RCV000188580 OR RCV000363602 OR RCV000678386 OR RCV001027839 OR RCV001847601 OR RCV002054437 OR RCV002272018 OR RCV002313707 OR RCV003230362 OR RCV003231103" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014449, RCV000014450, RCV000014451, RCV000014452, RCV000188580, RCV000363602, RCV000678386, RCV001027839, RCV001847601, RCV002054437, RCV002272018, RCV002313707, RCV003230362, RCV003231103" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014449...</a>
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<p>In a patient with autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions (PEOB1; <a href="/entry/258450">258450</a>), <a href="#23" class="mim-tip-reference" title="Lamantea, E., Tiranti, V., Bordoni, A., Toscano, A., Bono, F., Servidei, S., Papadimitriou, A., Spelbrink, H., Silvestri, L., Casari, G., Comi, G. P., Zeviani, M. <strong>Mutations of mitochondrial DNA polymerase gamma-A are a frequent cause of autosomal dominant or recessive progressive external ophthalmoplegia.</strong> Ann. Neurol. 52: 211-219, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12210792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12210792</a>] [<a href="https://doi.org/10.1002/ana.10278" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12210792">Lamantea et al. (2002)</a> identified compound heterozygosity for 2 mutations in the POLG gene: gly848-to-ser (G848S) and thr251-to-ile (T251I; <a href="#0007">174763.0007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12210792" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with PEO, <a href="#58" class="mim-tip-reference" title="Van Goethem, G., Lofgren, A., Dermaut, B., Ceuterick, C., Martin, J.-J., Van Broeckhoven, C. <strong>Digenic progressive external ophthalmoplegia in a sporadic patient: recessive mutations in POLG and C10orf2/Twinkle. (Letter)</strong> Hum. Mutat. 22: 175-176, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12872260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12872260</a>] [<a href="https://doi.org/10.1002/humu.10246" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12872260">Van Goethem et al. (2003)</a> identified a heterozygous G848S mutation in the POLG gene and a heterozygous arg334-to-gln mutation in the C10ORF2 gene (R334Q; <a href="/entry/606075#0008">606075.0008</a>), indicating a digenic mode of inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12872260" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 4 children with mitochondrial DNA depletion syndrome-4A (MTDPS4A; <a href="/entry/203700">203700</a>), manifest as Alpers syndrome, <a href="#6" class="mim-tip-reference" title="Davidzon, G., Mancuso, M., Ferraris, S., Quinzii, C., Hirano, M., Peters, H. L., Kirby, D., Thorburn, D. R., DiMauro, S. <strong>POLG mutations and Alpers syndrome.</strong> Ann. Neurol. 57: 921-924, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15929042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15929042</a>] [<a href="https://doi.org/10.1002/ana.20498" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15929042">Davidzon et al. (2005)</a> identified compound heterozygosity for 2 mutations in the POLG gene: G848S and W748S (<a href="#0013">174763.0013</a>). All patients died in childhood. <a href="#6" class="mim-tip-reference" title="Davidzon, G., Mancuso, M., Ferraris, S., Quinzii, C., Hirano, M., Peters, H. L., Kirby, D., Thorburn, D. R., DiMauro, S. <strong>POLG mutations and Alpers syndrome.</strong> Ann. Neurol. 57: 921-924, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15929042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15929042</a>] [<a href="https://doi.org/10.1002/ana.20498" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15929042">Davidzon et al. (2005)</a> noted that the G848S mutation occurs within the polymerase motif C of the enzyme. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15929042" 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="#38" class="mim-tip-reference" title="Nguyen, K. V., Ostergaard, E., Ravn, S. H., Balslev, T., Danielsen, E. R., Vardag, A., McKiernan, P. J., Gray, G., Naviaux, R. K. <strong>POLG mutations in Alpers syndrome.</strong> Neurology 65: 1493-1495, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16177225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16177225</a>] [<a href="https://doi.org/10.1212/01.wnl.0000182814.55361.70" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16177225">Nguyen et al. (2005)</a> reported 2 unrelated patients with mtDNA depletion syndrome-4A, manifest as Alpers syndrome. One was compound heterozygous for G848S and A467T (<a href="#0002">174763.0002</a>), and the other was compound heterozygous for G848S and W748S. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16177225" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Hakonen, A. H., Davidzon, G., Salemi, R., Bindoff, L. A., Van Goethem, G., DiMauro, S., Thorburn, D. R., Suomalainen, A. <strong>Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders.</strong> Europ. J. Hum. Genet. 15: 779-783, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17426723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17426723</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201831" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17426723">Hakonen et al. (2007)</a> presented evidence that the G848S disease chromosome originated from a common founder, possibly of European origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17426723" 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 infant with mtDNA depletion syndrome-4B (MTDPS4B; <a href="/entry/613662">613662</a>), manifest as severe hypotonia and gastrointestinal dysmotility (MNGIE), <a href="#11" class="mim-tip-reference" title="Giordano, C., Powell, H., Leopizzi, M., De Curtis, M., Travaglini, C., Sebastiani, M., Gallo, P., Taylor, R. W., d'Amati, G. <strong>Fatal congenital myopathy and gastrointestinal pseudo-obstruction due to POLG1 mutations.</strong> Neurology 72: 1103-1105, 2009. Note: Erratum: Neurology 73: 738 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19307547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19307547</a>] [<a href="https://doi.org/10.1212/01.wnl.0000345002.47396.e1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19307547">Giordano et al. (2009)</a> identified compound heterozygosity for 2 mutations in the POLG gene: G848S and a 697C-T transition, resulting in an arg227-to-trp (R227W; <a href="#0021">174763.0021</a>) substitution. Other features included hearing loss and clubfoot. Brain MRI showed enlarged ventricles, but leukoencephalopathy was not noted. There was no liver damage aside from that resulting from parenteral nutrition. 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<strong>.0007 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE 1</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014447 OR RCV000014448 OR RCV000020484 OR RCV000184009 OR RCV000188641 OR RCV000194055 OR RCV000262479 OR RCV000415105 OR RCV001004407 OR RCV001642225 OR RCV001678594 OR RCV001813742 OR RCV001813985 OR RCV001847602 OR RCV002271777 OR RCV002272019 OR RCV002313708 OR RCV002319423 OR RCV003458331 OR RCV003482402 OR RCV004584325 OR RCV005007846" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014447, RCV000014448, RCV000020484, RCV000184009, RCV000188641, RCV000194055, RCV000262479, RCV000415105, RCV001004407, RCV001642225, RCV001678594, RCV001813742, RCV001813985, RCV001847602, RCV002271777, RCV002272019, RCV002313708, RCV002319423, RCV003458331, RCV003482402, RCV004584325, RCV005007846" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014447...</a>
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<p>For discussion of the thr251-to-ile (T251I) mutation in the POLG gene that was found in compound heterozygous state in a patient with autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions (PEOB1; <a href="/entry/258450">258450</a>) by <a href="#23" class="mim-tip-reference" title="Lamantea, E., Tiranti, V., Bordoni, A., Toscano, A., Bono, F., Servidei, S., Papadimitriou, A., Spelbrink, H., Silvestri, L., Casari, G., Comi, G. P., Zeviani, M. <strong>Mutations of mitochondrial DNA polymerase gamma-A are a frequent cause of autosomal dominant or recessive progressive external ophthalmoplegia.</strong> Ann. Neurol. 52: 211-219, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12210792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12210792</a>] [<a href="https://doi.org/10.1002/ana.10278" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12210792">Lamantea et al. (2002)</a>, see <a href="#0006">174763.0006</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12210792" 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 2 sisters with mitochondrial DNA depletion syndrome-4B (MTDPS4B; <a href="/entry/613662">613662</a>), manifest as a neurogastrointestinal encephalopathy syndrome (<a href="#64" class="mim-tip-reference" title="Vissing, J., Ravn, K., Danielsen, E. R., Duno, M., Wibrand, F., Wevers, R. A., Schwartz, M. <strong>Multiple mtDNA deletions with features of MNGIE.</strong> Neurology 59: 926-929, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12297582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12297582</a>] [<a href="https://doi.org/10.1212/wnl.59.6.926" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12297582">Vissing et al., 2002</a>), <a href="#62" class="mim-tip-reference" title="Van Goethem, G., Schwartz, M., Lofgren, A., Dermaut, B., Van Broeckhoven, C., Vissing, J. <strong>Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy.</strong> Europ. J. Hum. Genet. 11: 547-549, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12825077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12825077</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12825077">Van Goethem et al. (2003)</a> identified 3 mutations in the POLG gene: a 752C-T transition in exon 3, resulting in a thr251-to-ile (T251I) substitution, a 1760C-T transition in exon 10, resulting in a pro587-to-leu substitution (P587L; <a href="#0011">174763.0011</a>), and a 2591A-T transversion in exon 16, resulting in an asn864-to-ser substitution (N864S; <a href="#0012">174763.0012</a>). The N864S mutation was in trans with the other 2 mutations; segregation in the family was consistent with the recessive nature of the 3 mutations, with the 2 sisters being compound heterozygotes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12825077+12297582" 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="#24" class="mim-tip-reference" title="Lamantea, E., Zeviani, M. <strong>Sequence analysis of familial PEO shows additional mutations associated with the 752C-T and 3527C-T changes in the POLG1 gene.</strong> Ann. Neurol. 56: 454-455, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15349879/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15349879</a>] [<a href="https://doi.org/10.1002/ana.20219" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15349879">Lamantea and Zeviani (2004)</a> identified the T251I mutation and the P587L mutation on the same allele in 3 families with autosomal recessive PEO (PEOB1; <a href="/entry/258450">258450</a>); each of the families was compound heterozygous for another POLG1 mutation in trans with the 2 cis alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15349879" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 affected patients from a family with mitochondrial DNA depletion syndrome-4A (<a href="/entry/203700">203700</a>), manifest as Alpers syndrome, <a href="#36" class="mim-tip-reference" title="Naviaux, R. K., Nguyen, K. V. <strong>POLG mutations associated with Alpers' syndrome and mitochondrial DNA depletion.</strong> Ann. Neurol. 55: 706-712, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15122711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15122711</a>] [<a href="https://doi.org/10.1002/ana.20079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15122711">Naviaux and Nguyen (2004)</a> identified compound heterozygosity for 2 mutations in the POLG gene: a 2899G-T transversion in exon 17 of the POLG gene, resulting in a glu873-to-ter (E873X) mutation, and A467T (<a href="#0002">174763.0002</a>). In the late stages of the disease, POLG activity was less than 5% of normal and mitochondrial DNA was depleted. An earlier report on these patients by <a href="#36" class="mim-tip-reference" title="Naviaux, R. K., Nguyen, K. V. <strong>POLG mutations associated with Alpers' syndrome and mitochondrial DNA depletion.</strong> Ann. Neurol. 55: 706-712, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15122711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15122711</a>] [<a href="https://doi.org/10.1002/ana.20079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15122711">Naviaux and Nguyen (2004)</a> had incorrectly stated that they were homozygous for the E873X mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15122711" 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">rs121918048 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918048;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=rs121918048" 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=rs121918048" 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=RCV000014454 OR RCV000758263 OR RCV001797046 OR RCV004700232 OR RCV004786259 OR RCV005007844" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014454, RCV000758263, RCV001797046, RCV004700232, RCV004786259, RCV005007844" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014454...</a>
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<p>In 2 Italian sibs with sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO; <a href="/entry/607459">607459</a>), <a href="#33" class="mim-tip-reference" title="Mancuso, M., Filosto, M., Bellan, M., Liguori, R., Montagna, P., Baruzzi, A., DiMauro, S., Carelli, V. <strong>POLG mutations causing ophthalmoplegia, sensorimotor polyneuropathy, ataxia, and deafness.</strong> Neurology 62: 316-318, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14745080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14745080</a>] [<a href="https://doi.org/10.1212/wnl.62.2.316" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14745080">Mancuso et al. (2004)</a> identified compound heterozygosity for 2 mutations in the POLG gene: a 2794C-T transition in exon 18, resulting in a his932-to-tyr (H932Y) substitution, and a 3151G-C transversion in exon 20, resulting in a gly1051-to-arg (G1051R; <a href="#0010">174763.0010</a>) substitution. Neither mutation was identified in 120 control alleles. Both mutations occur in highly conserved residues of the POLG gene that encode the polymerase region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14745080" 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> rs121918049 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918049;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/rs121918049?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=rs121918049" 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=rs121918049" 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=RCV000014455 OR RCV000188604 OR RCV000226986 OR RCV000778451 OR RCV002251905 OR RCV004760332 OR RCV005007845" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014455, RCV000188604, RCV000226986, RCV000778451, RCV002251905, RCV004760332, RCV005007845" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014455...</a>
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<p>For discussion of the gly1051-to-arg (G1051R) mutation that was found in compound heterozygous state in the POLG gene in 2 Italian sibs with sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO; <a href="/entry/607459">607459</a>) by <a href="#33" class="mim-tip-reference" title="Mancuso, M., Filosto, M., Bellan, M., Liguori, R., Montagna, P., Baruzzi, A., DiMauro, S., Carelli, V. <strong>POLG mutations causing ophthalmoplegia, sensorimotor polyneuropathy, ataxia, and deafness.</strong> Neurology 62: 316-318, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14745080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14745080</a>] [<a href="https://doi.org/10.1212/wnl.62.2.316" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14745080">Mancuso et al. (2004)</a>, see <a href="#0009">174763.0009</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14745080" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 MITOCHONDRIAL DNA DEPLETION SYNDROME 4B (MNGIE TYPE)</strong>
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PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE 1, INCLUDED
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POLG, PRO587LEU
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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> rs113994096 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994096;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/rs113994096?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=rs113994096" 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=rs113994096" 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=RCV000014456 OR RCV000020473 OR RCV000186576 OR RCV000193529 OR RCV000408293 OR RCV000415307 OR RCV000427845 OR RCV000508752 OR RCV001004602 OR RCV001610290 OR RCV001642226 OR RCV001813743 OR RCV001813986 OR RCV001847603 OR RCV002271777 OR RCV002313709 OR RCV002319424 OR RCV003458332 OR RCV003482402 OR RCV004584326" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014456, RCV000020473, RCV000186576, RCV000193529, RCV000408293, RCV000415307, RCV000427845, RCV000508752, RCV001004602, RCV001610290, RCV001642226, RCV001813743, RCV001813986, RCV001847603, RCV002271777, RCV002313709, RCV002319424, RCV003458332, RCV003482402, RCV004584326" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014456...</a>
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<p>For discussion of the pro587-to-leu (P587L) mutation in the POLG gene that was found in compound heterozygous state in 2 sisters with mitochondrial DNA depletion syndrome-4B (MTDPS4B; <a href="/entry/613662">613662</a>) by <a href="#62" class="mim-tip-reference" title="Van Goethem, G., Schwartz, M., Lofgren, A., Dermaut, B., Van Broeckhoven, C., Vissing, J. <strong>Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy.</strong> Europ. J. Hum. Genet. 11: 547-549, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12825077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12825077</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12825077">Van Goethem et al. (2003)</a>, see <a href="#0007">174763.0007</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12825077" 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="#9" class="mim-tip-reference" title="Filosto, M., Mancuso, M., Nishigaki, Y., Pancrudo, J., Harati, Y., Gooch, C., Mankodi, A., Bayne, L., Bonilla, E., Shanske, S., Hirano, M., DiMauro, S. <strong>Clinical and genetic heterogeneity in progressive external ophthalmoplegia due to mutations in polymerase-gamma.</strong> Arch. Neurol. 60: 1279-1284, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12975295/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12975295</a>] [<a href="https://doi.org/10.1001/archneur.60.9.1279" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12975295">Filosto et al. (2003)</a> identified the P587L mutation in 2 sibs with progressive external ophthalmoplegia, exercise intolerance, distal limb weakness, and peripheral neuropathy. One of the sibs also had abdominal cramping and gastrointestinal dysmotility suggesting MNGIE syndrome. An unrelated patient with the P587L mutation had progressive hearing loss, ataxia, PEO, distal myopathy, and hypogonadism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12975295" 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="#24" class="mim-tip-reference" title="Lamantea, E., Zeviani, M. <strong>Sequence analysis of familial PEO shows additional mutations associated with the 752C-T and 3527C-T changes in the POLG1 gene.</strong> Ann. Neurol. 56: 454-455, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15349879/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15349879</a>] [<a href="https://doi.org/10.1002/ana.20219" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15349879">Lamantea and Zeviani (2004)</a> identified the P587L mutation and the T251I mutation (<a href="#0007">174763.0007</a>) on the same allele in 3 families with autosomal recessive PEO (PEOB1; <a href="/entry/258450">258450</a>); each of the families was compound heterozygous for another POLG mutation in trans with the 2 cis alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15349879" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 MITOCHONDRIAL DNA DEPLETION SYNDROME 4B (MNGIE TYPE)</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121918050 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918050;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/rs121918050?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=rs121918050" 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=rs121918050" 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=RCV000014458 OR RCV002513043 OR RCV004586006 OR RCV005007847" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014458, RCV002513043, RCV004586006, RCV005007847" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014458...</a>
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<p>For discussion of the asn864-to-ser (N864S) mutation in the POLG gene that was found in compound heterozygous state in 2 sisters with mitochondrial DNA depletion syndrome-4B (MTDPS4B; <a href="/entry/613662">613662</a>) by <a href="#62" class="mim-tip-reference" title="Van Goethem, G., Schwartz, M., Lofgren, A., Dermaut, B., Van Broeckhoven, C., Vissing, J. <strong>Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy.</strong> Europ. J. Hum. Genet. 11: 547-549, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12825077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12825077</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12825077">Van Goethem et al. (2003)</a>, see <a href="#0007">174763.0007</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12825077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 SENSORY ATAXIC NEUROPATHY, DYSARTHRIA, AND OPHTHALMOPARESIS</strong>
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SPINOCEREBELLAR ATAXIA WITH EPILEPSY, INCLUDED<br />
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MITOCHONDRIAL DNA DEPLETION SYNDROME 4A (ALPERS TYPE), INCLUDED
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POLG, TRP748SER (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994097;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs113994097</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs113994097 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994097;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/rs113994097?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=rs113994097" 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=rs113994097" 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=RCV000014459 OR RCV000014460 OR RCV000014461 OR RCV000080023 OR RCV000144870 OR RCV000313739 OR RCV000507757 OR RCV000508846 OR RCV001198081 OR RCV002247336 OR RCV002313710 OR RCV003985719 OR RCV005007848" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014459, RCV000014460, RCV000014461, RCV000080023, RCV000144870, RCV000313739, RCV000507757, RCV000508846, RCV001198081, RCV002247336, RCV002313710, RCV003985719, RCV005007848" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014459...</a>
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<p>In 3 Finnish sibs with sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO; <a href="/entry/607459">607459</a>), previously reported by <a href="#41" class="mim-tip-reference" title="Rantamaki, M., Krahe, R., Paetau, A., Cormand, B., Mononen, I., Udd, B. <strong>Adult-onset autosomal recessive ataxia with thalamic lesions in a Finnish family.</strong> Neurology 57: 1043-1049, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11571332/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11571332</a>] [<a href="https://doi.org/10.1212/wnl.57.6.1043" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11571332">Rantamaki et al. (2001)</a>, <a href="#59" class="mim-tip-reference" title="Van Goethem, G., Luoma, P., Rantamaki, M., Al Memar, A., Kaakkola, S., Hackman, P., Krahe, R., Lofgren, A., Martin, J. J., De Jonghe, P., Suomalainen, A., Udd, B., Van Broeckhoven, C. <strong>POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement.</strong> Neurology 63: 1251-1257, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15477547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15477547</a>] [<a href="https://doi.org/10.1212/01.wnl.0000140494.58732.83" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15477547">Van Goethem et al. (2004)</a> identified a homozygous 2243G-C transversion in the POLG gene, resulting in a trp748-to-ser (W748S) substitution. The mutated residue lies within a highly conserved block of 6 amino acids that form a beta-sheet in the spacer, or linker, region of the enzyme and is presumed to be involved in primer-template interaction of the DNA polymerase. An unrelated Finnish patient had the same homozygous mutation, and an unrelated British patient was compound heterozygous for W748S and A467T (<a href="#0002">174763.0002</a>). In addition to the W748S mutation, all 5 patients carried a 3428A-G transition, resulting in a glu1143-to-gly (E1143G) substitution on the same allele. W748S was not identified in 168 Belgian and 70 Finnish controls; E1143G was identified in 11 Belgian and 3 Finnish controls. <a href="#59" class="mim-tip-reference" title="Van Goethem, G., Luoma, P., Rantamaki, M., Al Memar, A., Kaakkola, S., Hackman, P., Krahe, R., Lofgren, A., Martin, J. J., De Jonghe, P., Suomalainen, A., Udd, B., Van Broeckhoven, C. <strong>POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement.</strong> Neurology 63: 1251-1257, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15477547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15477547</a>] [<a href="https://doi.org/10.1212/01.wnl.0000140494.58732.83" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15477547">Van Goethem et al. (2004)</a> concluded that E1143G is a low-frequency polymorphism that forms a common ancestral haplotype; however, they noted that the contribution of E1143G to the phenotype was unclear. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11571332+15477547" 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 follow-up on the family reported by <a href="#41" class="mim-tip-reference" title="Rantamaki, M., Krahe, R., Paetau, A., Cormand, B., Mononen, I., Udd, B. <strong>Adult-onset autosomal recessive ataxia with thalamic lesions in a Finnish family.</strong> Neurology 57: 1043-1049, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11571332/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11571332</a>] [<a href="https://doi.org/10.1212/wnl.57.6.1043" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11571332">Rantamaki et al. (2001)</a> and <a href="#59" class="mim-tip-reference" title="Van Goethem, G., Luoma, P., Rantamaki, M., Al Memar, A., Kaakkola, S., Hackman, P., Krahe, R., Lofgren, A., Martin, J. J., De Jonghe, P., Suomalainen, A., Udd, B., Van Broeckhoven, C. <strong>POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement.</strong> Neurology 63: 1251-1257, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15477547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15477547</a>] [<a href="https://doi.org/10.1212/01.wnl.0000140494.58732.83" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15477547">Van Goethem et al. (2004)</a>, <a href="#42" class="mim-tip-reference" title="Rantamaki, M., Luoma, P., Virta, J. J., Rinne, J. O., Paetau, A., Suomalainen, A., Udd, B. <strong>Do carriers of POLG mutation W748S have disease manifestations?</strong> Clin. Genet. 72: 532-537, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17894835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17894835</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2007.00908.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17894835">Rantamaki et al. (2007)</a> found that heterozygous W748S carriers showed no clinically manifesting phenotype. Presumably unrelated neurologic signs and symptoms, including dementia, epilepsy, and migraine, were found in several carriers, but clearly defined neurologic diseases did not segregate with the mutation. The only notable finding was a subclinical axonal sensory neuropathy in the majority of carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17894835+11571332+15477547" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Hakonen, A. H., Heiskanen, S., Juvonen, V., Lappalainen, I., Luoma, P. T., Rantamaki, M., Van Goethem, G., Lofgren, A., Hackman, P., Paetau, A., Kaakkola, S., Majamaa, K., Varilo, T., Udd, B., Kaariainen, H., Bindoff, L. A., Suomalainen, A. <strong>Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal recessive ataxia with ancient European origin.</strong> Am. J. Hum. Genet. 77: 430-441, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16080118/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16080118</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16080118[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/10.1086/444548" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16080118">Hakonen et al. (2005)</a> found that the POLG allele with W748S and E1143G in cis is among the most common genetic causes of inherited ataxia in Finland. They identified 27 patients with mitochondrial recessive ataxia syndrome from 15 Finnish families, with a carrier frequency in the general population of 1:125. Since the mutation pair W748S+E1143G has also been described in European patients, they examined the haplotypes of 13 non-Finnish European patients with the W748S mutation. Haplotype analysis demonstrated that all the chromosomes carrying these 2 changes, in patients from Finland, Norway, the United Kingdom, and Belgium, originate from a common ancient founder. In Finland and Norway, long, common Northern haplotypes outside the core haplotype could be identified. Despite having identical homozygous mutations, the Finnish patients with this adult- or juvenile-onset disease had surprisingly heterogeneous phenotypes, albeit with a characteristic set of features, including ataxia, peripheral neuropathy, dysarthria, mild cognitive impairment, involuntary movements, psychiatric symptoms, and epileptic seizures. The high carrier frequency in Finland, the high number of patients in Norway, and the ancient European founder chromosome indicated that this form of ataxia should be considered in the first-line differential diagnosis of progressive ataxia syndromes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16080118" 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="#66" class="mim-tip-reference" title="Winterthun, S., Ferrari, G., He, L., Taylor, R. W., Zeviani, M., Turnbull, D. M., Engelsen, B. A., Moen, G., Bindoff, L. A. <strong>Autosomal recessive mitochondrial ataxic syndrome due to mitochondrial polymerase-gamma mutations.</strong> Neurology 64: 1204-1208, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15824347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15824347</a>] [<a href="https://doi.org/10.1212/01.WNL.0000156516.77696.5A" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15824347">Winterthun et al. (2005)</a> identified a homozygous W748S mutation in affected members from 2 families with a form of SANDO characterized by early onset of migraine headaches and/or seizures, and the later development of myoclonus (see SCAE; <a href="/entry/607459">607459</a>). Both patients were also homozygous for another putative disease-causing POLG mutation (Q497H; <a href="#0016">174763.0016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15824347" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 4 children with mitochondrial DNA depletion syndrome-4A (<a href="/entry/203700">203700</a>), manifest as Alpers syndrome, <a href="#6" class="mim-tip-reference" title="Davidzon, G., Mancuso, M., Ferraris, S., Quinzii, C., Hirano, M., Peters, H. L., Kirby, D., Thorburn, D. R., DiMauro, S. <strong>POLG mutations and Alpers syndrome.</strong> Ann. Neurol. 57: 921-924, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15929042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15929042</a>] [<a href="https://doi.org/10.1002/ana.20498" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15929042">Davidzon et al. (2005)</a> identified compound heterozygosity for 2 mutations in the POLG gene: W748S and G848S (<a href="#0006">174763.0006</a>). All patients died in childhood. <a href="#38" class="mim-tip-reference" title="Nguyen, K. V., Ostergaard, E., Ravn, S. H., Balslev, T., Danielsen, E. R., Vardag, A., McKiernan, P. J., Gray, G., Naviaux, R. K. <strong>POLG mutations in Alpers syndrome.</strong> Neurology 65: 1493-1495, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16177225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16177225</a>] [<a href="https://doi.org/10.1212/01.wnl.0000182814.55361.70" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16177225">Nguyen et al. (2005)</a> reported a patient with Alpers syndrome who was compound heterozygous for G848S and W748S. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16177225+15929042" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Hakonen, A. H., Davidzon, G., Salemi, R., Bindoff, L. A., Van Goethem, G., DiMauro, S., Thorburn, D. R., Suomalainen, A. <strong>Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders.</strong> Europ. J. Hum. Genet. 15: 779-783, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17426723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17426723</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201831" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17426723">Hakonen et al. (2007)</a> demonstrated that the disease W748S haplotype in patients from Australia and New Zealand derived from a common European haplotype. This haplotype shared a long region with the Finnish and Norwegian haplotype, but differed from Belgian and British patients, suggesting that the founder who formed the isolate in Australia and New Zealand may have been of Scandinavian rather than British origin. <a href="#13" class="mim-tip-reference" title="Hakonen, A. H., Davidzon, G., Salemi, R., Bindoff, L. A., Van Goethem, G., DiMauro, S., Thorburn, D. R., Suomalainen, A. <strong>Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders.</strong> Europ. J. Hum. Genet. 15: 779-783, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17426723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17426723</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201831" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17426723">Hakonen et al. (2007)</a> estimated that the common ancestor for the W748S haplotype lived more than 40 to 60 generations ago, before 1200 to 800 A.D. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17426723" 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> rs121918051 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918051;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/rs121918051?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=rs121918051" 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=rs121918051" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of 2 families, originating from a small village in northwest Sicily, with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions (PEOA1; <a href="/entry/157640">157640</a>), <a href="#23" class="mim-tip-reference" title="Lamantea, E., Tiranti, V., Bordoni, A., Toscano, A., Bono, F., Servidei, S., Papadimitriou, A., Spelbrink, H., Silvestri, L., Casari, G., Comi, G. P., Zeviani, M. <strong>Mutations of mitochondrial DNA polymerase gamma-A are a frequent cause of autosomal dominant or recessive progressive external ophthalmoplegia.</strong> Ann. Neurol. 52: 211-219, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12210792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12210792</a>] [<a href="https://doi.org/10.1002/ana.10278" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12210792">Lamantea et al. (2002)</a> identified a heterozygous 2869G-T transversion in the POLG gene, resulting in an ala957-to-ser (A957S) substitution. One patient in 1 of the families was homozygous for the A957S mutation and showed a more severe phenotype with earlier onset and a much higher amount of mtDNA deletions than his mildly affected heterozygous mother. Microsatellite analysis showed a common disease haplotype, supporting a common origin in these 2 families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12210792" 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> rs41549716 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs41549716;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/rs41549716?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=rs41549716" 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=rs41549716" 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=RCV000014463 OR RCV000175036 OR RCV000224425 OR RCV000464026 OR RCV001117866 OR RCV001847604 OR RCV002313711 OR RCV003985720" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014463, RCV000175036, RCV000224425, RCV000464026, RCV001117866, RCV001847604, RCV002313711, RCV003985720" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014463...</a>
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<p>This variant, formerly titled PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 1, has been reclassified as a variant of unknown significance based on the findings of <a href="#30" class="mim-tip-reference" title="Luoma, P. T., Eerola, J., Ahola, S., Hakonen, A. H., Hellstrom, O., Kivisto, K. T., Tienari, P. J., Suomalainen, A. <strong>Mitochondrial DNA polymerase gamma variants in idiopathic sporadic Parkinson disease.</strong> Neurology 69: 1152-1159, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17846414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17846414</a>] [<a href="https://doi.org/10.1212/01.wnl.0000276955.23735.eb" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17846414">Luoma et al. (2007)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17846414" 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 2 sibs with early-onset parkinsonism and PEOA1 (<a href="/entry/157640">157640</a>), <a href="#34" class="mim-tip-reference" title="Mancuso, M., Filosto, M., Oh, S. J., DiMauro, S. <strong>A novel polymerase-gamma mutation in a family with ophthalmoplegia, neuropathy, and parkinsonism.</strong> Arch. Neurol. 61: 1777-1779, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15534189/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15534189</a>] [<a href="https://doi.org/10.1001/archneur.61.11.1777" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15534189">Mancuso et al. (2004)</a> identified a heterozygous 2492A-G transition in exon 16 of the POLG gene, resulting in a tyr831-to-cys (Y831C) substitution. Parkinsonism was a prominent feature in both patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15534189" 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="#30" class="mim-tip-reference" title="Luoma, P. T., Eerola, J., Ahola, S., Hakonen, A. H., Hellstrom, O., Kivisto, K. T., Tienari, P. J., Suomalainen, A. <strong>Mitochondrial DNA polymerase gamma variants in idiopathic sporadic Parkinson disease.</strong> Neurology 69: 1152-1159, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17846414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17846414</a>] [<a href="https://doi.org/10.1212/01.wnl.0000276955.23735.eb" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17846414">Luoma et al. (2007)</a> identified the Y831C substitution in 5 controls, suggesting that it is a polymorphism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17846414" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0016 SPINOCEREBELLAR ATAXIA WITH EPILEPSY</strong>
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POLG, GLN497HIS
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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> rs121918052 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918052;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/rs121918052?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=rs121918052" 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=rs121918052" 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=RCV000014464 OR RCV000144870 OR RCV000528996 OR RCV000676325 OR RCV002496360 OR RCV003230363" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014464, RCV000144870, RCV000528996, RCV000676325, RCV002496360, RCV003230363" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014464...</a>
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<p>In affected members from 2 families with a form of SANDO characterized by early onset of migraine headaches and/or seizures, and the later development of myoclonus (see SCAE; <a href="/entry/607459">607459</a>), <a href="#66" class="mim-tip-reference" title="Winterthun, S., Ferrari, G., He, L., Taylor, R. W., Zeviani, M., Turnbull, D. M., Engelsen, B. A., Moen, G., Bindoff, L. A. <strong>Autosomal recessive mitochondrial ataxic syndrome due to mitochondrial polymerase-gamma mutations.</strong> Neurology 64: 1204-1208, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15824347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15824347</a>] [<a href="https://doi.org/10.1212/01.WNL.0000156516.77696.5A" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15824347">Winterthun et al. (2005)</a> identified a homozygous 1491G-C transversion in the POLG gene, resulting in a gln497-to-his (Q497H) substitution. Both patients were also homozygous for another disease-causing POLG mutation (W748S; <a href="#0013">174763.0013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15824347" 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>.0017 MITOCHONDRIAL DNA DEPLETION SYNDROME 4A (ALPERS TYPE)</strong>
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POLG, TRP1020TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1567185775 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1567185775;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=rs1567185775" 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=rs1567185775" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014465" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014465" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014465</a>
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<p>In 2 sisters with mitochondrial DNA depletion syndrome-4A (MTDPS4A; <a href="/entry/203700">203700</a>), manifest as Alpers syndrome, <a href="#38" class="mim-tip-reference" title="Nguyen, K. V., Ostergaard, E., Ravn, S. H., Balslev, T., Danielsen, E. R., Vardag, A., McKiernan, P. J., Gray, G., Naviaux, R. K. <strong>POLG mutations in Alpers syndrome.</strong> Neurology 65: 1493-1495, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16177225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16177225</a>] [<a href="https://doi.org/10.1212/01.wnl.0000182814.55361.70" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16177225">Nguyen et al. (2005)</a> identified compound heterozygosity for 2 mutations in the POLG gene: a 3339G-A transition in exon 19, resulting in a trp1020-to-ter (W1020X) substitution, and A467T (<a href="#0002">174763.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16177225" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0018" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0018 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE 1</strong>
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POLG, ARG853TRP
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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> rs121918053 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918053;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/rs121918053?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=rs121918053" 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=rs121918053" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014466 OR RCV000560575 OR RCV001449754 OR RCV003330388 OR RCV003333951 OR RCV005007849" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014466, RCV000560575, RCV001449754, RCV003330388, RCV003333951, RCV005007849" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014466...</a>
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<p>In 2 Italian sisters with early-onset parkinsonism, peripheral sensory neuropathy, and mitochondrial DNA deletions but without PEO (PEOB1; <a href="/entry/258450">258450</a>), <a href="#5" class="mim-tip-reference" title="Davidzon, G., Greene, P., Mancuso, M., Klos, K. J., Ahlskog, J. E., Hirano, M., DiMauro, S. <strong>Early-onset familial parkinsonism due to POLG mutations.</strong> Ann. Neurol. 59: 859-862, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16634032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16634032</a>] [<a href="https://doi.org/10.1002/ana.20831" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16634032">Davidzon et al. (2006)</a> identified compound heterozygosity for 2 mutations in the POLG gene: a 2839C-T transition in exon 16 resulting in an arg853-to-trp (R853W) substitution and a 2491G-C transversion in exon 13 resulting in a gly737-to-arg (G737R; <a href="#0019">174763.0019</a>) substitution. The R853W and G737R substitutions occurred in the polymerase domain and the linker region, respectively. Each unaffected parent was heterozygous for 1 of the mutations. Despite the absence of PEO, the phenotype was most consistent with the clinical features of that disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16634032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0019" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0019 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE 1</strong>
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</span>
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</h4>
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POLG, GLY737ARG
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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> rs121918054 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918054;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/rs121918054?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=rs121918054" 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=rs121918054" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014467 OR RCV000188568 OR RCV000233045 OR RCV000370280 OR RCV000508744 OR RCV000768053 OR RCV001004601 OR RCV001813987 OR RCV001847605 OR RCV002316196 OR RCV003318542 OR RCV003985721" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014467, RCV000188568, RCV000233045, RCV000370280, RCV000508744, RCV000768053, RCV001004601, RCV001813987, RCV001847605, RCV002316196, RCV003318542, RCV003985721" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014467...</a>
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<p>For discussion of the gly737-to-arg (G737R) mutation in the POLG gene that was found in compound heterozygous state in 2 Italian sisters with autosomal recessive progressive external ophthalmopletia with mitochondrial DNA deletions (PEOB1; <a href="/entry/258450">258450</a>) by <a href="#5" class="mim-tip-reference" title="Davidzon, G., Greene, P., Mancuso, M., Klos, K. J., Ahlskog, J. E., Hirano, M., DiMauro, S. <strong>Early-onset familial parkinsonism due to POLG mutations.</strong> Ann. Neurol. 59: 859-862, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16634032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16634032</a>] [<a href="https://doi.org/10.1002/ana.20831" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16634032">Davidzon et al. (2006)</a>, see <a href="#0018">174763.0018</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16634032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0020 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 1</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">rs121918055 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918055;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=rs121918055" 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=rs121918055" 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=RCV000014468" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014468" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014468</a>
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<p>In 6 affected members of a large family with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions (PEOA1; <a href="/entry/157640">157640</a>), <a href="#17" class="mim-tip-reference" title="Hudson, G., Schaefer, A. M., Taylor, R. W., Tiangyou, W., Gibson, A., Venables, G., Griffiths, P., Burn, D. J., Turnbull, D. M., Chinnery, P. F. <strong>Mutation of the linker region of the polymerase-gamma-1 (POLG1) gene associated with progressive external ophthalmoplegia and parkinsonism.</strong> Arch. Neurol. 64: 553-557, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17420318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17420318</a>] [<a href="https://doi.org/10.1001/archneur.64.4.553" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17420318">Hudson et al. (2007)</a> identified a heterozygous 1532G-A transition in exon 8 of the POLG gene, resulting in a ser511-to-asn (S511N) substitution in the linker region of the protein. The substitution was not identified in 192 control chromosomes or 248 disease control subjects. The S511N pathogenic mutation was found on the same allele as an intronic variant (2070+158G-A), which the authors considered unlikely to have functional consequences. All patients had ptosis, and 1 had external ophthalmoplegia. The 69-year-old asymptomatic sister of the index patient also carried the S511N mutation, suggesting incomplete penetrance. The female index patient had ataxia, hearing loss, and sensory axonal neuropathy. Her son also had hearing loss and parkinsonism and was found to have a second POLG variant (1389G-A) on the other allele, but both his carrier sister and obligate carrier father had no reported neurologic abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17420318" 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>.0021 MITOCHONDRIAL DNA DEPLETION SYNDROME 4B (MNGIE TYPE)</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121918056 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918056;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/rs121918056?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=rs121918056" 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=rs121918056" 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=RCV000014469 OR RCV000255169 OR RCV000525480 OR RCV000787362 OR RCV002513044 OR RCV004586007 OR RCV005007850" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014469, RCV000255169, RCV000525480, RCV000787362, RCV002513044, RCV004586007, RCV005007850" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014469...</a>
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<p>For discussion of the arg227-to-trp (R227W) mutation in the POLG gene that was found in compound heterozygous state in an infant with mtDNA depletion syndrome-4B (MTDPS4B; <a href="/entry/613662">613662</a>) by <a href="#11" class="mim-tip-reference" title="Giordano, C., Powell, H., Leopizzi, M., De Curtis, M., Travaglini, C., Sebastiani, M., Gallo, P., Taylor, R. W., d'Amati, G. <strong>Fatal congenital myopathy and gastrointestinal pseudo-obstruction due to POLG1 mutations.</strong> Neurology 72: 1103-1105, 2009. Note: Erratum: Neurology 73: 738 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19307547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19307547</a>] [<a href="https://doi.org/10.1212/01.wnl.0000345002.47396.e1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19307547">Giordano et al. (2009)</a>, see <a href="#0006">174763.0006</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19307547" 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>.0022 MITOCHONDRIAL DNA DEPLETION SYNDROME 4A (ALPERS TYPE)</strong>
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MITOCHONDRIAL DNA DEPLETION SYNDROME 4B (MNGIE TYPE), INCLUDED
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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> rs267606959 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606959;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/rs267606959?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=rs267606959" 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=rs267606959" 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=RCV000014470 OR RCV000014471 OR RCV000188673" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014470, RCV000014471, RCV000188673" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014470...</a>
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<p><a href="#22" class="mim-tip-reference" title="Kurt, B., Jaeken, J., Van Hove, J., Lagae, L., Lofgren, A., Everman, D. B., Jayakar, P., Naini, A., Wierenga, K. J., Van Goethem, G., Copeland, W. C., DiMauro, S. <strong>A novel POLG gene mutation in 4 children with Alpers-like hepatocerebral syndromes.</strong> Arch. Neurol. 67: 239-244, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20142534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20142534</a>] [<a href="https://doi.org/10.1001/archneurol.2009.332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20142534">Kurt et al. (2010)</a> identified a 3218C-T transition in exon 20 of the POLG gene, resulting in a pro1073-to-leu (P1073L) substitution, in compound heterozygosity with another pathogenic POLG mutation in 4 patients who all had a hepatocerebral disorder with psychomotor delay, seizures, and liver disease, consistent with mitochondrial DNA depletion syndrome-4A (MTDPS4A; <a href="/entry/203700">203700</a>), manifest as Alpers syndrome. The P1073L mutation occurred in a conserved residue in the polymerase domain of the protein. An unrelated girl and boy were compound heterozygous for the P1073L and A467T (<a href="#0002">174763.0002</a>) mutations. Both had developmental delay. The girl was hypotonic at birth, and later had short stature, neurosensory hearing loss, celiac disease, liver dysfunction with hepatic fibrosis, and gastrointestinal pseudoobstruction with dysmotility, reminiscent of the allelic disorder MNGIE syndrome (MTDPS4B; <a href="/entry/613662">613662</a>). Brain MRI showed signal abnormalities in the basal ganglia and thalami. She died at age 9 years. RT-PCR showed severe mtDNA depletion in liver tissue (72.1% depletion compared to controls). The boy had status epilepticus with coma, cholestasis, optic atrophy, hyperplastic gastropathy with gastric ulcer, and death at age 3 years, 4 months. In addition, 2 boys were compound heterozygous for the P1073L and W748S (<a href="#0013">174763.0013</a>) and G848S (<a href="#0006">174763.0006</a>) mutations, respectively. The first child had severe attention-deficit/hyperactivity disorder with motor and verbal tics, status epilepticus with coma and myoclonus, liver dysfunction, and cavitation in the cerebrum, thalamus, cerebellum, and basal ganglia. He died at age 13 years. The other child had poor growth, hypotonia, seizures, and intestinal hypomotility and died at age 10 months. Muscle tissue showed mtDNA depletion (64%). <a href="#22" class="mim-tip-reference" title="Kurt, B., Jaeken, J., Van Hove, J., Lagae, L., Lofgren, A., Everman, D. B., Jayakar, P., Naini, A., Wierenga, K. J., Van Goethem, G., Copeland, W. C., DiMauro, S. <strong>A novel POLG gene mutation in 4 children with Alpers-like hepatocerebral syndromes.</strong> Arch. Neurol. 67: 239-244, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20142534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20142534</a>] [<a href="https://doi.org/10.1001/archneurol.2009.332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20142534">Kurt et al. (2010)</a> emphasized the phenotypic variability associated with POLG mutations, and noted that various signs and symptoms can occur in each associated disorder. Three of the children with the P1073L mutation also had gastrointestinal dysmotility, suggesting that this mutation may be associated with that particular feature. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20142534" 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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Ashley, N., O'Rourke, A., Smith, C., Adams, S., Gowda, V., Zeviani, M., Brown, G. K., Fratter, C., Poulton, J.
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<strong>Depletion of mitochondrial DNA in fibroblast cultures from patients with POLG1 mutations is a consequence of catalytic mutations.</strong>
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Hum. Molec. Genet. 17: 2496-2506, 2008. Note: Erratum: Hum. Molec. Genet. 18: 4905-4906, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18487244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18487244</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18487244[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=18487244" 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/ddn150" target="_blank">Full Text</a>]
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Bertazzoni, U., Scovassi, A. I., Brun, G. M.
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<strong>Chick-embryo DNA polymerase gamma: identity of gamma-polymerases purified from nuclei and mitochondria.</strong>
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Europ. J. Biochem. 81: 237-248, 1977.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/563788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">563788</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=563788" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1432-1033.1977.tb11945.x" target="_blank">Full Text</a>]
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Bird, T. D., Shaw, C. M.
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<strong>Progressive myoclonus and epilepsy with dentatorubral degeneration: a clinicopathological study of the Ramsay Hunt syndrome.</strong>
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J. Neurol. Neurosurg. Psychiat. 41: 140-149, 1978.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/632821/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">632821</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=632821" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jnnp.41.2.140" target="_blank">Full Text</a>]
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Bogenhagen, D. F., Rousseau, D., Burke, S.
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[<a href="https://doi.org/10.1074/jbc.M708444200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.20831" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.20498" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000092303.13864.be" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/brain/awh410" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.60.9.1279" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000345002.47396.e1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.63.1.107" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17426723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17426723</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17426723" 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/sj.ejhg.5201831" target="_blank">Full Text</a>]
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<strong>Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal recessive ataxia with ancient European origin.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16080118/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16080118</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16080118[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=16080118" 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/10.1086/444548" target="_blank">Full Text</a>]
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<a id="Hance2005" class="mim-anchor"></a>
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Hum. Molec. Genet. 14: 1775-1783, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15888483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15888483</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15888483" 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/ddi184" target="_blank">Full Text</a>]
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<strong>POLG1, C10ORF2, and ANT1 mutations are uncommon in sporadic progressive external ophthalmoplegia with multiple mitochondrial DNA deletions.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16682683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16682683</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16682683" 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.0000210486.32196.24" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17420318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17420318</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17420318" 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.64.4.553" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38570685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38570685</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=38570685[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=38570685" 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/s41586-024-07260-z" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15702133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15702133</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15702133" 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/sj.ejhg.5201341" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2010.12.012" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000140494.58732.83" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 08/14/2024
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Matthew B. Gross - updated : 03/18/2024<br>Bao Lige - updated : 03/14/2024<br>Cassandra L. Kniffin - updated : 10/10/2016<br>Cassandra L. Kniffin - updated : 3/23/2016<br>Ada Hamosh - updated : 10/25/2013<br>George E. Tiller - updated : 8/21/2013<br>Cassandra L. Kniffin - updated : 10/26/2011<br>Cassandra L. Kniffin - updated : 12/10/2010<br>Cassandra L. Kniffin - updated : 5/11/2010<br>Cassandra L. Kniffin - updated : 8/27/2009<br>Cassandra L. Kniffin - updated : 7/9/2009<br>Cassandra L. Kniffin - updated : 6/1/2009<br>George E. Tiller - updated : 11/14/2008<br>George E. Tiller - updated : 10/28/2008<br>Patricia A. Hartz - updated : 9/24/2008<br>Ada Hamosh - updated : 4/23/2008<br>Cassandra L. Kniffin - updated : 1/29/2008<br>Cassandra L. Kniffin - updated : 12/27/2007<br>Cassandra L. Kniffin - updated : 12/14/2007<br>Cassandra L. Kniffin - updated : 10/1/2007<br>Cassandra L. Kniffin - updated : 9/12/2007<br>Cassandra L. Kniffin - updated : 2/15/2007<br>Cassandra L. Kniffin - updated : 6/20/2006<br>Ada Hamosh - updated : 11/14/2005<br>Cassandra L. Kniffin - updated : 10/13/2005<br>Cassandra L. Kniffin - updated : 8/31/2005<br>Victor A. McKusick - updated : 8/18/2005<br>Ada Hamosh - updated : 8/15/2005<br>Cassandra L. Kniffin - updated : 6/9/2005<br>Victor A. McKusick - updated : 4/26/2005<br>John A. Phillips, III - updated : 4/25/2005<br>Cassandra L. Kniffin - updated : 3/30/2005<br>Cassandra L. Kniffin - updated : 2/21/2005<br>Marla J. F. O'Neill - updated : 11/4/2004<br>Cassandra L. Kniffin - updated : 8/31/2004<br>Ada Hamosh - updated : 7/22/2004<br>Cassandra L. Kniffin - updated : 1/9/2004<br>Victor A. McKusick - updated : 7/21/2003<br>Cassandra L. Kniffin - updated : 6/20/2003<br>Victor A. McKusick - updated : 10/19/2001<br>Ada Hamosh - updated : 6/28/2001<br>Rebekah S. Rasooly - updated : 4/7/1998<br>Victor A. McKusick - updated : 3/16/1998
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<a id="creationDate" class="mim-anchor"></a>
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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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<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 : 1/3/1991
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</span>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 08/16/2024
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</span>
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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 : 08/15/2024<br>carol : 08/14/2024<br>alopez : 03/19/2024<br>mgross : 03/18/2024<br>mgross : 03/14/2024<br>carol : 08/16/2019<br>alopez : 10/11/2016<br>ckniffin : 10/10/2016<br>carol : 03/28/2016<br>carol : 3/25/2016<br>carol : 3/24/2016<br>ckniffin : 3/23/2016<br>carol : 7/29/2015<br>ckniffin : 7/23/2015<br>carol : 7/23/2015<br>alopez : 10/25/2013<br>alopez : 8/21/2013<br>terry : 7/5/2012<br>carol : 10/27/2011<br>ckniffin : 10/26/2011<br>terry : 2/17/2011<br>terry : 2/17/2011<br>terry : 2/15/2011<br>carol : 1/3/2011<br>carol : 12/21/2010<br>ckniffin : 12/20/2010<br>carol : 12/20/2010<br>ckniffin : 12/10/2010<br>wwang : 5/14/2010<br>ckniffin : 5/11/2010<br>wwang : 10/30/2009<br>ckniffin : 8/27/2009<br>wwang : 8/3/2009<br>ckniffin : 7/9/2009<br>wwang : 6/10/2009<br>ckniffin : 6/1/2009<br>wwang : 11/14/2008<br>wwang : 10/28/2008<br>mgross : 9/25/2008<br>terry : 9/24/2008<br>alopez : 4/25/2008<br>terry : 4/23/2008<br>wwang : 2/4/2008<br>ckniffin : 1/29/2008<br>wwang : 1/14/2008<br>ckniffin : 12/27/2007<br>wwang : 12/20/2007<br>ckniffin : 12/14/2007<br>wwang : 10/4/2007<br>ckniffin : 10/1/2007<br>wwang : 9/21/2007<br>ckniffin : 9/12/2007<br>wwang : 2/21/2007<br>ckniffin : 2/15/2007<br>wwang : 6/22/2006<br>ckniffin : 6/20/2006<br>alopez : 11/15/2005<br>terry : 11/14/2005<br>carol : 10/20/2005<br>ckniffin : 10/13/2005<br>terry : 10/12/2005<br>wwang : 9/19/2005<br>wwang : 9/6/2005<br>ckniffin : 8/31/2005<br>alopez : 8/24/2005<br>terry : 8/18/2005<br>carol : 8/16/2005<br>terry : 8/15/2005<br>wwang : 6/15/2005<br>ckniffin : 6/9/2005<br>tkritzer : 4/29/2005<br>terry : 4/26/2005<br>alopez : 4/25/2005<br>carol : 3/30/2005<br>ckniffin : 3/29/2005<br>ckniffin : 2/21/2005<br>ckniffin : 2/21/2005<br>ckniffin : 1/4/2005<br>carol : 11/4/2004<br>tkritzer : 11/4/2004<br>carol : 9/7/2004<br>ckniffin : 8/31/2004<br>tkritzer : 8/13/2004<br>ckniffin : 8/4/2004<br>alopez : 7/23/2004<br>terry : 7/22/2004<br>tkritzer : 2/18/2004<br>ckniffin : 2/6/2004<br>tkritzer : 1/14/2004<br>ckniffin : 1/9/2004<br>carol : 10/31/2003<br>tkritzer : 9/15/2003<br>tkritzer : 9/9/2003<br>cwells : 7/31/2003<br>cwells : 7/31/2003<br>terry : 7/21/2003<br>carol : 7/9/2003<br>ckniffin : 6/20/2003<br>alopez : 11/21/2001<br>cwells : 10/23/2001<br>cwells : 10/23/2001<br>terry : 10/19/2001<br>carol : 6/29/2001<br>carol : 6/29/2001<br>carol : 6/28/2001<br>carol : 6/8/2000<br>mgross : 5/22/2000<br>psherman : 4/7/1998<br>psherman : 3/16/1998<br>terry : 3/4/1998<br>supermim : 3/16/1992<br>carol : 2/22/1992<br>carol : 1/9/1991<br>carol : 1/3/1991
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</span>
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<span class="mim-font">
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<strong>*</strong> 174763
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<div>
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<h3>
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<span class="mim-font">
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POLYMERASE, DNA, GAMMA; POLG
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</div>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<div>
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<h4>
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<span class="mim-font">
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POLYMERASE, DNA, GAMMA-1; POLG1<br />
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POLG, CATALYTIC SUBUNIT<br />
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POLG-ALPHA; POLGA
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</span>
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</h4>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: POLG</em></strong>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 20415001, 699328003, 717266001;
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<strong>ICD10CM:</strong> G31.81;
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</span>
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</p>
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<br />
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<strong>
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<em>
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Cytogenetic location: 15q26.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 15:89,316,320-89,334,824 </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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<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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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<tbody>
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<td rowspan="5">
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<span class="mim-font">
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15q26.1
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<td>
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<span class="mim-font">
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Mitochondrial DNA depletion syndrome 4A (Alpers type)
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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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203700
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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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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">
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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">
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Mitochondrial DNA depletion syndrome 4B (MNGIE type)
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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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613662
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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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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">
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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">
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Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE)
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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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607459
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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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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">
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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">
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Progressive external ophthalmoplegia, autosomal dominant 1
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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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157640
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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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Autosomal dominant
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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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3
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<tr>
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<td>
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<span class="mim-font">
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Progressive external ophthalmoplegia, autosomal recessive 1
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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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258450
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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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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">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Lestienne (1987) provided evidence for a role of DNA polymerase gamma (POLG) in the replication of human mitochondrial DNA. Bertazzoni et al. (1977) showed that the enzyme was present in both the nucleus and the mitochondria. Mitochondrial POLG is a homotetramer; see POLG2 (604983). </p><p>Based on the sequences of the S. cerevisiae and S. pombe Polg genes, Ropp and Copeland (1996) cloned the human and Drosophila POLG genes and a partial chicken Polg cDNA. The human POLG cDNA, isolated from a HeLa cell cDNA library, encodes a predicted 1,239-amino acid protein that is 78% identical to chicken Polg in the polymerase domain. Antibodies against the polymerase domain of human POLG detected a 140-kD mitochondrial protein on Western blots and immunoprecipitated a protein with POLG-like activity from mitochondrial extracts. The authors found a potentially unstable CAG repeat in the first exon of the human POLG gene. </p><p>Zullo et al. (1997) identified cloned cDNA and genomic sequences as human mitochondrial POLG by homology with the catalytic subunit of yeast mitochondrial DNA polymerase. Lecrenier et al. (1997) cloned a human POLG cDNA by searching for ESTs with homology to yeast Polg (Mip1p). The human and yeast POLG proteins are 43% identical. Human POLG is expressed as a 4.5- to 5.0-kb mRNA that is most abundant in skeletal muscle and heart. </p><p><strong><em>POLG Alternative Reading Frame</em></strong></p><p>
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Loughran et al. (2020) determined that the POLG mRNA is a dual-coding mRNA that encodes both POLG and POLGARF (620759). The POLGARF alternative reading frame (-1), which overlaps extensively with the POLG reading frame, is initiated by a CUG triplet 52 nucleotides upstream of the POLG start codon and produces a 260-amino acid POLGARF protein. The 5-prime leader of the POLG mRNA contains a 23-codon conserved AUG-initiated upstream ORF (uORF), and translation of this uORF governs the ratio between POLG and POLGARF synthesized from the single POLG mRNA. For further information on POLGARF, see 620759. </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>The POLG protein is composed of a C-terminal polymerase ('pol') domain and an amino-terminal exonuclease ('exo') domain. The exo domain increases the fidelity of mitochondrial DNA replication by conferring a proofreading activity to the enzyme (Lamantea et al., 2002). </p><p>Mitochondrial nucleoids are large complexes containing, on average, 5 to 7 mtDNA genomes and several proteins involved in mtDNA replication and transcription, as well as related processes. Bogenhagen et al. (2008) had previously shown that POLG was associated with native purified HeLa cell nucleoids. Using a formaldehyde crosslinking technique, they found that POLG copurified with mtDNA and was a core nucleoid protein. Bogenhagen et al. (2008) confirmed these findings by Western blot analysis. </p><p>Shestakova et al. (2023) noted that EIF4G2 (602325) promotes translation of mRNAs with long 5-prime leaders and uORFs via reinitiation after uORF translation or by substituting for EIF4G1 (600495) to promote leaky scanning through the translated uORF after loss of EIF4G1. They found that the uORF in the POLG/POLGARF mRNA made translation of both POLG and POLGARF reliant on EIF4G2. EIF4G2 enhanced both leaky scanning and reinitiation, and it appeared that ribosomes could acquire EIF4G2 during the early steps of reinitiation. Shestakova et al. (2023) concluded that EIF4G2 is a multifunctional scanning guardian that replaces EIF4G1 to facilitate ribosome movement but not ribosome attachment to mRNAs with uORFs, like POLG/POLGARF. </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>By FISH, Zullo et al. (1997) mapped the POLG gene to 15q24-q26 and the mouse Polg gene to chromosome 7. Walker et al. (1997) mapped the POLG gene to 15q25 by FISH. </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>Del Bo et al. (2003) presented evidence suggesting that mutations in the exonuclease domain of POLG, which is responsible for the proofreading activity of the protein, result in a high frequency of rare, randomly distributed mtDNA point mutations. </p><p>Rovio et al. (1999) demonstrated that the common allele for the trinucleotide CAG repeat within the coding sequence of the POLG gene is 10 CAG repeats. This allele is found in different ethnic groups at a uniformly high frequency (0.88) and is absent in only approximately 1% of individuals, suggesting that it may be maintained by selection. </p><p>Tang et al. (2011) identified mutations in the POLG gene in 136 (5%) of 2,697 patients analyzed because of a wide range of clinical features suggestive of a POLG-related disorder, including lactic acidosis, seizures, ataxia, peripheral neuropathy, developmental delay, myopathy, chronic progressive external ophthalmoplegia, or hepatopathy. Ninety-two patients had biallelic mutations, 3 had heterozygous dominant mutations, and 41 had 1 heterozygous mutation with a second mutant allele unidentified. A467T (174763.0002) was the most common mutation, accounting for 23% of mutant alleles. </p><p>Stumpf et al. (2010) identified dominant and recessive changes in mtDNA mutagenesis and depletion and mitochondrial dysfunction caused by 31 mutations in the conserved regions of the mip1 gene, which encodes the Saccharomyces cerevisiae ortholog of human POLG. Twenty mip1 mutant enzymes were shown to disrupt mtDNA replication, implicating their orthologous human mutations in disease. Five theretofore uncharacterized sporadic POLG mutations caused decreased polymerase activity leading to mtDNA depletion and mitochondrial dysfunction. Most mitochondrial-defective mip1 mutants displayed reduced or depleted mtDNA, and the severity of the phenotype of the mip1 mutant strain correlated with the age of onset of disease associated with the human ortholog. Increasing nucleotide pools by overexpression of ribonucleotide reductase (RNR1; 180450) suppressed mtDNA replication defects caused by several dominant mip1 mutations, and the orthologous human mutations revealed severe nucleotide binding defects. </p><p>Kang et al. (2024) investigated the role of the W748S mutation in the POLG1 gene in response to viral infection. Fibroblasts from patients with homozygosity for the W748S mutation were exposed to double-stranded RNA (dsRNA) and double-stranded DNA (dsDNA), which were used as a mimic of pathogenic-associated molecular patterns of viruses. Patient fibroblasts displayed a dampened interferon-beta response and an exaggerated proinflammatory response compared to control cells. Furthermore, patient fibroblasts had reduced mtDNA and mtRNA in the cell cytoplasm after dsDNA and dsRNA exposure compared to controls. Exposure of patient cells to the HSV1 virus resulted in enhanced expression of an early regulatory protein of HSV1 (ICP27), decreased POLG1 protein levels, decreased mtDNA levels, a dampened interferon response, and induction of phosphorylated MLKL, which activates necroptosis. Exposure of patient cells to the tick-born encephalitis virus (TBEV) and SARS-CoV-2 viruses also resulted in decreased POLG1 protein expression and increased phosphorylated MLKL, but an exaggerated interferon response. Kang et al. (2024) concluded that the W748S mutation in POLG1 results in an abnormal immune response to 3 different viruses favoring viral replication in the early infection phase, a delayed, overactivated proinflammatory response, and increased sensitivity to necroptosis. </p><p><strong><em>Progressive External Ophthalmoplegia (PEO) with Mitochondrial DNA Deletions</em></strong></p><p>
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Van Goethem et al. (2001) identified a missense mutation (Y955C; 174763.0001) in the polymerase motif B of the POLG gene in a family segregating autosomal dominant progressive external ophthalmoplegia (PEOA1; 157640). A tyrosine at position 955 is highly conserved in DNA polymerases of different species, including the orthologous enzymes in yeast and Drosophila. In 2 families with evidence of autosomal recessive PEO (PEOB1; 258450), Van Goethem et al. (2001) found compound heterozygosity for 2 different missense mutations (see 174763.0002-174763.0004) in the POLG gene. </p><p>Van Goethem et al. (2003) reported compound heterozygosity for 2 mutations in the POLG gene (A467T, 174763.0002 and R627W, 174763.0005) in a patient with the clinical triad of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO; 607459). The finding indicated that SANDO is a variant of autosomal recessive PEO. Winterthun et al. (2005) identified homozygosity for the A467T mutation in affected members from 2 families with a form of SANDO characterized by early onset of migraine headaches and/or seizures, and the later development of myoclonus (see SCAE, 607459). </p><p>POLG1 is the only polymerase known to be involved in replication of mtDNA. Kollberg et al. (2005) investigated whether mtDNA point mutations are involved, directly or indirectly, in the pathogenesis of PEO. Muscle biopsy specimens from patients with POLG1 mutations, affecting either the exonuclease or the polymerase domain, were investigated. Long-range PCR revealed multiple mtDNA deletions in all the patients but not in controls. No point mutations were identified in single COX-deficient muscle fibers. Cloning and sequencing of muscle homogenate identified randomly distributed point mutations at a very low frequency in patients and controls. Kollberg et al. (2005) concluded that mtDNA point mutations are not directly or indirectly involved in the pathogenesis of mitochondrial disease in patients with different POLG1 mutations. </p><p>Gonzalez-Vioque et al. (2006) identified mutations in the POLG gene in 6 (25%) of 24 patients with mitochondrial disease and muscle mtDNA deletions. Five patients had PEO; however, 1 patient, who had a mutation which was previously reported as a polymorphism, showed only mild distal muscle atrophy without ophthalmoplegia. </p><p>Hudson et al. (2006) identified mutations in the POLG gene in 3 (8%) of 38 patients with sporadic PEO. No mutations were identified in the ANT1 (103220) or C10ORF2 (606075) genes. </p><p><strong><em>Mitochondrial DNA Depletion Syndrome 4A (Alpers Type)</em></strong></p><p>
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Naviaux and Nguyen (2004) reported 3 patients with mitochondrial DNA depletion syndrome-4A (MTDPS4A; 203700), manifest as Alpers syndrome, who were homozygous for a mutation (E873X; 174763.0008) in the POLG gene. They later published a correction (Naviaux and Nguyen, 2005) stating that 2 affected patients from 1 family with Alpers syndrome were compound heterozygous for 2 mutations in the POLG gene: E873X and A467T (174763.0002). Naviaux and Nguyen (2005) stated that the existence of a common 4-bp insertion in the POLG gene yielded the incorrect initial results. </p><p>In 4 patients with mtDNA depletion syndrome-4A, manifest as Alpers syndrome, Davidzon et al. (2005) identified compound heterozygosity for 2 mutations in the POLG gene (174763.0006 and 174763.0013). Liver biopsies from 3 patients showed mitochondrial DNA depletion ranging from 87 to 94%, and all 4 patients showed decreased activity of mtDNA-encoded respiratory chain complexes. </p><p>Ferrari et al. (2005) identified mutations in the POLG gene in 8 patients with Alpers syndrome and 1 patient with a nonspecific severe floppy infant syndrome associated with liver failure. </p><p><strong><em>Mitochondrial DNA Depletion Syndrome 4B (MNGIE Type)</em></strong></p><p>
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In 2 sisters with mitochondrial DNA depletion syndrome-4B (MTDPS4B; 613662), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) (Vissing et al., 2002), Van Goethem et al. (2003) identified 3 mutations in the POLG gene: T251I (174763.0007), P587L (174763.0011), and N864S (174763.0012). The N864S mutation was in trans with the other 2 mutations; segregation in the family was consistent with the recessive nature of the 3 mutations, with the 2 sisters being compound heterozygotes. </p><p>In an infant with severe hypotonia, gastrointestinal dysmotility, and mtDNA depletion in muscle, Giordano et al. (2009) identified compound heterozygosity for 2 mutations in the POLG gene (G848S, 174763.0006 and R227W, 174763.0021). Other features included hearing loss and clubfoot. Brain MRI showed enlarged ventricles, but leukoencephalopathy was not noted. The patient died at age 20 days from respiratory failure. There was no liver damage aside from that resulting from parenteral nutrition. Analysis of the bowel showed that mtDNA depletion was confined mainly to the external layer of the muscularis propria. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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Rovio et al. (2001) genotyped infertile and control males for POLG CAG-repeat lengths. Using sperm DNA from persons in whom azoospermia was excluded, they found 9 of 99 infertile males (9%) from Finland or England to be homozygous for the absence of the 10 CAG repeat common allele. In contrast, the common allele was present in sperm DNA from all 98 fertile males studied, as well as in all but 6 of 522 healthy controls whose blood DNA was analyzed in parallel. Based on standard Hardy-Weinberg predictions, the 'homozygous mutant' genotype (absence of the common allele, whether or not this reflected homozygosity for a particular mutant allele) should be found in approximately 1.7% of individuals. They found the genotype at a frequency slightly below expectation in the general population, although this deviation was not statistically significant. In contrast, their finding that the 'homozygous mutant' genotype occurred in 9 of 99 infertile but 0 of 98 fertile males was highly significant. They also found a higher frequency of heterozygosity in infertile males (35%) than in fertile males (18%) or in the general population (23%). Some infertile males may be compound heterozygotes, with a second mutation elsewhere in the gene. Infertile males homozygous for the POLG mutant genotype were below the commonly accepted thresholds for at least 2 out of 3 sperm quality parameters. The POLG genotype in blood and sperm was similar in these individuals, thus excluding any effect of de novo tissue-specific mutation. Polyglutamine tracts are commonly regarded as interfaces for protein-protein interactions; thus, a sperm-specific protein could interact with this region of POLG. Given the many rounds of cell division during spermatogenesis and the functional necessity of mtDNA for sperm function, it seems plausible that a suboptimal mtDNA polymerase could result in the accumulation of mtDNA mutations and in failure to complete differentiation. The mutant allele had 11 CAG repeats as the nodal frequency (see Fig. 1 of Rovio et al. (2001)). </p><p>In a study of 195 infertile patients and 190 normospermic men of Italian origin, Krausz et al. (2004) found the 10 CAG repeat allele of the POLG gene in 85% of infertile and 81% of fertile controls. Mean values of sperm parameters such as sperm count, motility, and morphology did not differ significantly between repeat allele carriers and controls. The authors concluded that their study failed to confirm any influence of the POLG gene polymorphism on the efficiency of spermatogenesis and that analysis of the CAG repeat tract of the POLG gene does not appear to have any clinical diagnostic value. </p>
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<strong>Genotype/Phenotype Correlations</strong>
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</h4>
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<p>The most severe manifestations of defects of the POLG protein have been associated with mutations of the 'spacer' region of POLG. Luoma et al. (2005) identified a family segregating 3 POLG amino acid variants: A467T (174763.0002), R627Q, and Q1236H. The first 2 affect the spacer region, and the third is a polymorphism, allelic with R627Q. Three grades of disease severity appeared to correlate with the genotypes. The patient with the most severe outcome, cerebellar ataxia syndrome, had all 3 variants; those with R627Q and Q1236H had juvenile-onset ptosis and gait disturbance; those with a single A467T allele had late-onset ptosis. Biochemical analysis of expressed mutant proteins revealed that the A467T substitution resulted in decreased activity, DNA binding, and processivity of the polymerase. Other pathogenic spacer mutants showed DNA-binding affinities and processivities similar to or higher than the controls, suggesting that the disease-causing mechanisms of spacer mutations may extend beyond the basic catalytic functions of POLG. </p><p>Stewart et al. (2009) identified 27 POLG mutations in 14 probands with a variety of phenotypes, including PEO, Alpers syndrome, and ataxia. All 6 patients with Alpers syndrome carried at least 1 mutation in the linker region of the protein (A467T, or W748S; 174763.0013). </p><p>In a study of the cellular phenotype derived from 24 children with biallelic POLG1 mutations, 21 of whom had a clinical diagnosis of mitochondrial DNA depletion syndrome-4A, manifest as Alpers syndrome, Ashley et al. (2008) found that the cellular mtDNA content reflected the genotype. Those with mtDNA depletion in the liver and/or muscle had at least 1 missense or nonsense mutation in a catalytic domain, either the polymerase or exonuclease region. Four of 12 patients further analyzed showed a progressive, mosaic pattern of mtDNA depletion in fibroblasts, and all had biallelic mutations in catalytic domains. These patients had a severe clinical phenotype with early onset before 1 year of age, hepatic involvement, and death by 16 months of age. Their cells showed respiratory chain defects. Patients with 2 mutations in the linker region of the gene did not show mtDNA depletion and had the mildest phenotype with onset in childhood or adolescence and little liver involvement. The study also found that the average mtDNA content declined with serial passage in cell culture in patients with mtDNA depletion, which Ashley et al. (2008) postulated was a result of mtDNA replication stalling, indicating the requirement for both catalytic actions of POLG1 in mitochondrial replication. </p><p>Sohl et al. (2013) performed functional studies of 4 different missense mutations in the POLG gene that are associated with variable phenotypic severity ranging from death in infancy from Alpers syndrome to mild PEO. The mutations from most to least severe were A957P, R1096C, R1096H, and A957S (174763.0014); all mutations occurred in the polymerase domain of the catalytic subunit. The mutations did not strongly affect the affinity for the DNA substrate. However, in functional studies, the A957P mutant showed the most striking deficiencies in the incorporation of a correct dNTP compared to wildtype, the R1096C and R1096H showed variable but intermediate defects, and the A957S mutant showed only a small decrease in efficiency, which matched the disease severity associated with the mutations. In addition, the A957P mutant had a 2-fold order of magnitude loss of fidelity compared to wildtype, suggesting that a buildup of mitochondrial mutations may contribute to death in infancy in those with this mutation. </p>
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<strong>Population Genetics</strong>
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<p>Hakonen et al. (2007) demonstrated that the A467T disease chromosomes of patients from Australia, New Zealand, and the United States shared a common haplotype with European patients, indicating that they all derived from a common European founder. The Norwegian A467T disease haplotype diverged from the European founder earlier than the other haplotypes. Hakonen et al. (2007) estimated that the common ancestor for A467T lived more than 15 to 30 generations ago, before 1700 to 1400 A.D. Similarly, the disease W748S haplotype in patients from Australia and New Zealand derived from a common European haplotype. This haplotype shared a long region with the Finnish and Norwegian haplotype but differed from Belgian and British patients, suggesting that the W748S founder who formed the isolate in Australia and New Zealand may have been of Scandinavian rather than British origin. The common ancestor for the W748S haplotype lived more than 40 to 60 generations ago, before 1200 to 800 A.D. There was also evidence of a common founder, possibly of European origin, for the G848S (174763.0006) mutation. The findings suggested that these mutations did not result from recurrent mutation events but were rather caused by spreading of single founder mutations. </p>
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<strong>Animal Model</strong>
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<p>Trifunovic et al. (2004) created homozygous knockin mice that expressed a proofreading-deficient version of PolgA, the nucleus-encoded catalytic subunit of mtDNA polymerase. The knockin mice developed an mtDNA mutator phenotype with a 3- to 5-fold increase in the levels of point mutations, as well as increased amounts of deleted mtDNA. This increase in somatic mtDNA mutations is associated with reduced life span and premature onset of aging-related phenotypes such as weight loss, reduced subcutaneous fat, alopecia, kyphosis, osteoporosis, anemia, reduced fertility, and heart enlargement. Trifunovic et al. (2004) concluded that their results provided a causative link between mtDNA mutations and aging phenotypes in mammals. </p><p>Kujoth et al. (2005) demonstrated that the mice generated by Trifunovic et al. (2004) (D257A mice) accumulated mtDNA mutations and display features of accelerated aging. Accumulation of mtDNA mutations was not associated with increased markers of oxidative stress or a defect in cellular proliferation, but was correlated with the induction of apoptotic markers, particularly in tissues characterized by rapid cell turnover. The levels of apoptotic markers were also found to increase during aging in normal mice. Kujoth et al. (2005) concluded that accumulation of mtDNA mutations that promote apoptosis may be a central mechanism driving mammalian aging. </p><p>Miller (2005) and Gershon (2005) questioned whether the phenotype of aging described by Kujoth et al. (2005) was really an accelerated aging phenotype. Some of the mice exhibited severe anemia and loss of intestinal crypt cells not commonly seen in aged mice. Prolla and Weindruch (2005) commented that hearing loss and sarcopenia as seen in the D257A mice are commonly observed in aging and that the more severe phenotype such as anemia and loss of intestinal crypts are likely to be secondary to complete stem cell depletion, which is not observed in normal aging. </p><p>Hance et al. (2005) demonstrated that PolgA deficiency in mouse embryos caused an early developmental arrest between embryonic days 7.5 and 8.5 associated with severe mtDNA depletion. PolgA +/- mice had half the wildtype levels of PolgA transcripts and a slight reduction in mtDNA levels, but developed normally. PolgA transcripts in PolgA +/- mice increased in response to artificially elevated mtDNA copy number, revealing a possible regulatory link between mtDNA maintenance and PolgA expression. Hance et al. (2005) concluded that Polg indeed is the only DNA polymerase capable of maintaining mtDNA in mammalian mitochondria, and appears to be essential for the organogenesis during mammalian embryonic development. </p><p>Vermulst et al. (2008) identified mitochondrial DNA deletions as a driving force behind the premature aging phenotype of the mitochondrial mutator mice developed by Trifunovic et al. (2004). Vermulst et al. (2008) provided evidence for homology-directed DNA repair mechanism in mitochondria that is directly linked to the formation of mitochondrial DNA deletions. In addition, their results demonstrated that the rate at which mitochondrial DNA mutations reach phenotypic expression differs markedly among tissues, which may be an important factor in determining the tolerance of a tissue to random mitochondrial mutagenesis. Mitochondrial mutator mice showed a 7- to 11-fold increase in mitochondrial DNA deletions over those in wildtype mice or mice heterozygous for this PolgA mutation. Vermulst et al. (2008) found that duodenum, heart, and brain tissue from prematurely aging PolgA homozygous mutator mice contained many COX-negative cells. </p><p>Using a series of mouse mutants to investigate the extent to which inherited mtDNA mutations can contribute to aging, Ross et al. (2013) found that maternally transmitted mtDNA mutations can induce mild aging phenotypes in mice with a wildtype nuclear genome. Maternally transmitted mtDNA mutations led to anticipation of reduced fertility in mice that were heterozygous for the mtDNA mutator allele (PolgA-wt/mut) and aggravated premature aging phenotypes in mtDNA mutator mice (PolgA-mut/mut). Unexpectedly, a combination of maternally transmitted and somatic mtDNA mutations also led to stochastic brain malformations. Ross et al. (2013) concluded that a preexisting mutation load will not only allow somatic mutagenesis to create a critically high total mtDNA mutation load sooner but will also increase clonal expansion mtDNA mutations to enhance the normally occurring mosaic respiratory chain deficiency in aging tissues. </p><p>Kang et al. (2024) generated mutant mice homozygous for an allele with 2 mutations in the Polg1 gene, W726S+E1121G, corresponding to the human POLG1 allele with W748S and E1143G (see 174763.0013). The mutant mice had decreased treadmill performance as well as decreased mitochondrial content in various tissues and decreased mtDNA content in the liver. Mice that were infected with tick-born encephalitis virus (TBEV) demonstrated decreased interferon-1 (see 147660) pathway signaling and increased proinflammatory signaling compared to controls. Following infection, the mutant mice developed abnormal depletion of nucleotide and mtDNA pools, which are known to be necessary in viral replication. Brains of infected mice demonstrated reduction of GABAergic neurons. Livers of infected mutant mice were inflamed, with increased expression of the necroptosis marker phosphorylated MLKL (615153) and decreased POLG1 expression. Furthermore, elevated levels of IL6 (147620) were detected in mutant mouse serum. Kang et al. (2024) concluded that the mutant Polg1 allele resulted in an aberrant innate immune response to viral infection, resulting in depletion of GABAergic neurons and liver necrosis. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>22 Selected Examples):</strong>
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<strong>.0001 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 1</strong>
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</h4>
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POLG, TYR955CYS
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SNP: rs113994099,
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ClinVar: RCV000014439, RCV000508934, RCV000676321, RCV000758267, RCV003478975
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<p>In affected members of a 3-generation Belgian pedigree with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions (PEOA1; 157640), Van Goethem et al. (2001) identified a 2864A-G transition in the POLG gene, resulting in a tyr955-to-cys (Y955C) substitution in the polymerase B domain of the protein. The tyrosine at codon 955 is highly conserved. Segregation analysis showed complete cosegregation of Y955C with autosomal dominant PEO (maximum lod = 4.01 at theta = 0.0). The mutation was present in the 8 patients and 2 of 15 at-risk individuals; it was absent in 432 control chromosomes. </p><p>Lamantea et al. (2002) identified the heterozygous Y955C mutation in 5 unrelated families with adPEO. Four families were Italian and 1 was from Greece; 1 of the Italian families was originally reported by Zeviani et al. (1989) and Servidei et al. (1991). Microsatellite analysis did not identify a common disease haplotype in these families. </p><p>To analyze the effects of the Y955C mutation on the kinetics and fidelity of DNA synthesis, Ponamarev et al. (2002) expressed the Y955C mutant protein in Sf9 cells by site-directed mutagenesis. The Y955C enzyme retained a wildtype catalytic rate and demonstrated a 45-fold decrease in apparent binding affinity for the incoming nucleoside triphosphate, but the authors noted that mitochondrial matrix pools are usually high enough to overcome this reduced affinity. Fidelity studies showed that the Y955C derivative was 2-fold less accurate for basepair substitutions than wildtype, even with proofreading activity. Genetic inactivation of the exonuclease revealed a 10- to 100-fold increase in mismatch errors. Ponamarev et al. (2002) presented a model in which the enhanced error rate of the mutant enzyme promotes mtDNA deletions, as seen in PEO, via a slippage mechanism. </p><p>In affected members of 4 adPEO families, including the Swedish family originally reported by Lundberg (1962), Luoma et al. (2004) identified the heterozygous Y955C mutation. </p>
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<span class="mim-font">
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<strong>.0002 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE 1</strong>
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SENSORY ATAXIC NEUROPATHY, DYSARTHRIA, AND OPHTHALMOPARESIS, INCLUDED<br />
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SPINOCEREBELLAR ATAXIA WITH EPILEPSY, INCLUDED<br />
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MITOCHONDRIAL DNA DEPLETION SYNDROME 4A (ALPERS TYPE), INCLUDED
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POLG, ALA467THR
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SNP: rs113994095,
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gnomAD: rs113994095,
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ClinVar: RCV000014440, RCV000014441, RCV000014442, RCV000014443, RCV000184011, RCV000188658, RCV000347876, RCV000508942, RCV001004604, RCV001095683, RCV001198082, RCV001376079, RCV001731286, RCV001813983, RCV001847600, RCV002273931, RCV002316195
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<span class="mim-text-font">
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<p>In a family with 3 affected sibs with autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletion (PEOB1; 258450), Van Goethem et al. (2001) identified compound heterozygosity for 2 missense mutations in the POLG gene: a 1399G-A transition, resulting in an ala467-to-thr (A467T) substitution, and a 911T-G transversion, resulting in a leu304-to-arg substitution (L304R; 174763.0003). In 2 affected individuals in another family, Van Goethem et al. (2001) identified the A467T mutation in compound heterozygous state with an 8G-C transversion, resulting in an arg3-to-pro substitution (R3P; 174763.0004). Three of 229 control individuals were heterozygous for A467T (allele T frequency of 0.6%). The R3P mutation was not observed in any of the control individuals. The A467T mutation occurs in the linker region of the protein (Stewart et al., 2009). </p><p>Van Goethem et al. (2003) stated that the A467T mutation has a frequency of 0.6% in the Belgian population and that sensory neuropathy is the initial feature in Belgian compound heterozygous autosomal recessive progressive external ophthalmoplegia patients, all carrying the POLG A467T mutation in combination with another mutation. </p><p>Van Goethem et al. (2003) reported a patient who was homozygous for the A467T mutation, which they incorrectly reported as ALA476THR. (Van Broeckhoven (2004) reported the correct mutation as A467T.) At age 15 years, the patient experienced mild ataxia, and later developed myoclonus, seizures, and sensory neuropathy. External ophthalmoplegia was absent on repeated examinations. Muscle biopsy did not show any abnormalities, including no ragged-red fibers, but long-range PCR detected a low proportion of mtDNA deletions in the patient's muscle. Van Goethem et al. (2003) noted that the clinical features in this patient were unique and suggested that some features overlapped with the syndrome of myoclonus, epilepsy, and ragged-red fibers (MERRF; 545000). </p><p>In 3 sibs with sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO; 607459), originally reported by Rantamaki et al. (2001), Van Goethem et al. (2004) identified homozygosity for the A467T mutation. An unrelated British patient was compound heterozygous for the A467T mutation and W748S (174763.0013). An unrelated Belgian patient with a variant form of SANDO without ophthalmoparesis was also homozygous for the A467T mutation. That patient had psychiatric symptoms, severe gastroparesis, and dilated cardiomyopathy, illustrating the variable clinical phenotype that can result from recessive POLG mutations. </p><p>In 2 affected patients from a family with mitochondrial DNA depletion syndrome-4A (MTDPS4A; 203700), manifest as Alpers syndrome, Naviaux and Nguyen (2005) identified compound heterozygosity for 2 mutations in the POLG gene: A467T and E873X (174763.0008). An earlier report on these patients by Naviaux and Nguyen (2004) had incorrectly stated that they were homozygous for the E873X mutation. </p><p>In 2 sisters with mtDNA depletion syndrome manifest as Alpers syndrome, Nguyen et al. (2005) identified compound heterozygosity for 2 mutations in the POLG gene: a A467T and W1020X (174763.0017). Two affected sibs from another family with Alpers syndrome were compound heterozygous for A467T and G848S (174763.0006). Another child with Alpers syndrome from an unrelated family who was homozygous for the A467T mutation showed late-onset at age 8.5 years and death by age 9 years. </p><p>Winterthun et al. (2005) identified homozygosity for the A467T mutation in affected members from 2 families with a form of SANDO characterized by early onset of migraine headaches and/or seizures, and the later development of myoclonus (see SCAE; 607459). </p><p>Hakonen et al. (2007) demonstrated that the A467T disease chromosomes of patients from Australia, New Zealand, and the United States shared a common haplotype with European patients, indicating that they all derived from a common European founder. Further analysis indicated that the Norwegian A467T disease haplotype diverged from the European founder earlier than the other haplotypes. Hakonen et al. (2007) estimated that the common ancestor for A467T lived more than 15 to 30 generations ago, before 1700 to 1400 A.D. </p><p>By reevaluation of 2 sibs reported by Bird and Shaw (1978), who were classified as having progressive myoclonic epilepsy-5 (EPM5; see 607459), Sandford et al. (2016) identified compound heterozygous mutations in the POLG gene (A467T on 1 allele and W748S, 174763.0013 and G497H, 174763.0016 in cis on the other allele). In these sibs, Tao et al. (2011) had previously identified 2 heterozygous missense variants in the PRICKLE2 gene (608501.0001) that occurred on the same allele. Furthermore, Sandford et al. (2016) showed that the 2 heterozygous missense variants in the PRICKLE2 gene identified by Tao et al. (2011) occurred on opposite chromosomes, which would be more consistent with recessive inheritance. Sandford et al. (2016) concluded that the phenotype in these patients resulted from the POLG mutations and not from the PRICKLE2 variants. In a response, Mahajan and Bassuk (2016) maintained that the PRICKLE2 variants identified by Tao et al. (2011) contributed to the phenotype in their patients. </p>
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</span>
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</div>
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<div>
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE 1</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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POLG, LEU304ARG
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<br />
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SNP: rs121918044,
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gnomAD: rs121918044,
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ClinVar: RCV000014444, RCV000188648, RCV000626287, RCV000762954, RCV001266602, RCV001813984, RCV003387722, RCV005007843
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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 leu304-to-arg (L304R) mutation in the POLG gene that was found in compound heterozygous state in 3 sibs with autosomal recessive progressive ophthalmoplegia with mitochondrial DNA deletions (PEOB1; 258450) by Van Goethem et al. (2001), see 174763.0002. </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>.0004 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE 1</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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POLG, ARG3PRO
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<br />
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SNP: rs121918045,
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ClinVar: RCV000014445
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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 arg3-to-pro (R3P) mutation in the POLG gene that was found in compound heterozygous state in 2 members of a family with autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions (PEOB1; 258450) by Van Goethem et al. (2001), see 174763.0002. </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>.0005 SENSORY ATAXIC NEUROPATHY, DYSARTHRIA, AND OPHTHALMOPARESIS</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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POLG, ARG627TRP
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<br />
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SNP: rs121918046,
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gnomAD: rs121918046,
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ClinVar: RCV000014446, RCV001382679, RCV001781264, RCV004579531, RCV005003357
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a sporadic case of SANDO (607459), Van Goethem et al. (2003) found compound heterozygosity for 2 mutations in the POLG gene: A467T (174763.0002) and arg627-to-trp (R627W). The R627W mutation came from the father, and the A467T mutation from the mother. </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 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE 1</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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PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, DIGENIC, INCLUDED<br />
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MITOCHONDRIAL DNA DEPLETION SYNDROME 4A (ALPERS TYPE), INCLUDED<br />
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MITOCHONDRIAL DNA DEPLETION SYNDROME 4B (MNGIE TYPE), INCLUDED
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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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POLG, GLY848SER
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<br />
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SNP: rs113994098,
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gnomAD: rs113994098,
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ClinVar: RCV000014449, RCV000014450, RCV000014451, RCV000014452, RCV000188580, RCV000363602, RCV000678386, RCV001027839, RCV001847601, RCV002054437, RCV002272018, RCV002313707, RCV003230362, RCV003231103
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions (PEOB1; 258450), Lamantea et al. (2002) identified compound heterozygosity for 2 mutations in the POLG gene: gly848-to-ser (G848S) and thr251-to-ile (T251I; 174763.0007). </p><p>In a patient with PEO, Van Goethem et al. (2003) identified a heterozygous G848S mutation in the POLG gene and a heterozygous arg334-to-gln mutation in the C10ORF2 gene (R334Q; 606075.0008), indicating a digenic mode of inheritance. </p><p>In 4 children with mitochondrial DNA depletion syndrome-4A (MTDPS4A; 203700), manifest as Alpers syndrome, Davidzon et al. (2005) identified compound heterozygosity for 2 mutations in the POLG gene: G848S and W748S (174763.0013). All patients died in childhood. Davidzon et al. (2005) noted that the G848S mutation occurs within the polymerase motif C of the enzyme. </p><p>Nguyen et al. (2005) reported 2 unrelated patients with mtDNA depletion syndrome-4A, manifest as Alpers syndrome. One was compound heterozygous for G848S and A467T (174763.0002), and the other was compound heterozygous for G848S and W748S. </p><p>Hakonen et al. (2007) presented evidence that the G848S disease chromosome originated from a common founder, possibly of European origin. </p><p>In an infant with mtDNA depletion syndrome-4B (MTDPS4B; 613662), manifest as severe hypotonia and gastrointestinal dysmotility (MNGIE), Giordano et al. (2009) identified compound heterozygosity for 2 mutations in the POLG gene: G848S and a 697C-T transition, resulting in an arg227-to-trp (R227W; 174763.0021) substitution. Other features included hearing loss and clubfoot. Brain MRI showed enlarged ventricles, but leukoencephalopathy was not noted. There was no liver damage aside from that resulting from parenteral nutrition. Analysis of the bowel showed that mtDNA depletion was mainly confined to the external layer of the muscularis propria. </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>.0007 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE 1</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">
|
|
MITOCHONDRIAL DNA DEPLETION SYNDROME 4B (MNGIE TYPE), INCLUDED
|
|
</span>
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</div>
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<div>
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<span class="mim-text-font">
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POLG, THR251ILE
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<br />
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SNP: rs11394094, rs113994094,
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gnomAD: rs113994094,
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ClinVar: RCV000014447, RCV000014448, RCV000020484, RCV000184009, RCV000188641, RCV000194055, RCV000262479, RCV000415105, RCV001004407, RCV001642225, RCV001678594, RCV001813742, RCV001813985, RCV001847602, RCV002271777, RCV002272019, RCV002313708, RCV002319423, RCV003458331, RCV003482402, RCV004584325, RCV005007846
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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>For discussion of the thr251-to-ile (T251I) mutation in the POLG gene that was found in compound heterozygous state in a patient with autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions (PEOB1; 258450) by Lamantea et al. (2002), see 174763.0006. </p><p>In 2 sisters with mitochondrial DNA depletion syndrome-4B (MTDPS4B; 613662), manifest as a neurogastrointestinal encephalopathy syndrome (Vissing et al., 2002), Van Goethem et al. (2003) identified 3 mutations in the POLG gene: a 752C-T transition in exon 3, resulting in a thr251-to-ile (T251I) substitution, a 1760C-T transition in exon 10, resulting in a pro587-to-leu substitution (P587L; 174763.0011), and a 2591A-T transversion in exon 16, resulting in an asn864-to-ser substitution (N864S; 174763.0012). The N864S mutation was in trans with the other 2 mutations; segregation in the family was consistent with the recessive nature of the 3 mutations, with the 2 sisters being compound heterozygotes. </p><p>Lamantea and Zeviani (2004) identified the T251I mutation and the P587L mutation on the same allele in 3 families with autosomal recessive PEO (PEOB1; 258450); each of the families was compound heterozygous for another POLG1 mutation in trans with the 2 cis alleles. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 MITOCHONDRIAL DNA DEPLETION SYNDROME 4A (ALPERS TYPE)</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
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POLG, GLU873TER
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<br />
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|
|
SNP: rs121918047,
|
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|
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ClinVar: RCV000014453
|
|
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|
|
</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 affected patients from a family with mitochondrial DNA depletion syndrome-4A (203700), manifest as Alpers syndrome, Naviaux and Nguyen (2004) identified compound heterozygosity for 2 mutations in the POLG gene: a 2899G-T transversion in exon 17 of the POLG gene, resulting in a glu873-to-ter (E873X) mutation, and A467T (174763.0002). In the late stages of the disease, POLG activity was less than 5% of normal and mitochondrial DNA was depleted. An earlier report on these patients by Naviaux and Nguyen (2004) had incorrectly stated that they were homozygous for the E873X mutation. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 SENSORY ATAXIC NEUROPATHY, DYSARTHRIA, AND OPHTHALMOPARESIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLG, HIS932TYR
|
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|
|
|
<br />
|
|
|
|
SNP: rs121918048,
|
|
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|
|
|
|
|
ClinVar: RCV000014454, RCV000758263, RCV001797046, RCV004700232, RCV004786259, RCV005007844
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 Italian sibs with sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO; 607459), Mancuso et al. (2004) identified compound heterozygosity for 2 mutations in the POLG gene: a 2794C-T transition in exon 18, resulting in a his932-to-tyr (H932Y) substitution, and a 3151G-C transversion in exon 20, resulting in a gly1051-to-arg (G1051R; 174763.0010) substitution. Neither mutation was identified in 120 control alleles. Both mutations occur in highly conserved residues of the POLG gene that encode the polymerase region. </p>
|
|
</span>
|
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</div>
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 SENSORY ATAXIC NEUROPATHY, DYSARTHRIA, AND OPHTHALMOPARESIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLG, GLY1051ARG
|
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|
<br />
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|
|
SNP: rs121918049,
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|
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|
|
gnomAD: rs121918049,
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|
|
|
|
|
ClinVar: RCV000014455, RCV000188604, RCV000226986, RCV000778451, RCV002251905, RCV004760332, RCV005007845
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the gly1051-to-arg (G1051R) mutation that was found in compound heterozygous state in the POLG gene in 2 Italian sibs with sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO; 607459) by Mancuso et al. (2004), see 174763.0009. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
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<br />
|
|
</div>
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 MITOCHONDRIAL DNA DEPLETION SYNDROME 4B (MNGIE TYPE)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE 1, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLG, PRO587LEU
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|
<br />
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|
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SNP: rs113994096,
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|
|
gnomAD: rs113994096,
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|
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|
|
ClinVar: RCV000014456, RCV000020473, RCV000186576, RCV000193529, RCV000408293, RCV000415307, RCV000427845, RCV000508752, RCV001004602, RCV001610290, RCV001642226, RCV001813743, RCV001813986, RCV001847603, RCV002271777, RCV002313709, RCV002319424, RCV003458332, RCV003482402, RCV004584326
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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>For discussion of the pro587-to-leu (P587L) mutation in the POLG gene that was found in compound heterozygous state in 2 sisters with mitochondrial DNA depletion syndrome-4B (MTDPS4B; 613662) by Van Goethem et al. (2003), see 174763.0007. </p><p>Filosto et al. (2003) identified the P587L mutation in 2 sibs with progressive external ophthalmoplegia, exercise intolerance, distal limb weakness, and peripheral neuropathy. One of the sibs also had abdominal cramping and gastrointestinal dysmotility suggesting MNGIE syndrome. An unrelated patient with the P587L mutation had progressive hearing loss, ataxia, PEO, distal myopathy, and hypogonadism. </p><p>Lamantea and Zeviani (2004) identified the P587L mutation and the T251I mutation (174763.0007) on the same allele in 3 families with autosomal recessive PEO (PEOB1; 258450); each of the families was compound heterozygous for another POLG mutation in trans with the 2 cis alleles. </p>
|
|
</span>
|
|
</div>
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<div>
|
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<br />
|
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</div>
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|
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 MITOCHONDRIAL DNA DEPLETION SYNDROME 4B (MNGIE TYPE)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
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POLG, ASN864SER
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<br />
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SNP: rs121918050,
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gnomAD: rs121918050,
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ClinVar: RCV000014458, RCV002513043, RCV004586006, RCV005007847
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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 asn864-to-ser (N864S) mutation in the POLG gene that was found in compound heterozygous state in 2 sisters with mitochondrial DNA depletion syndrome-4B (MTDPS4B; 613662) by Van Goethem et al. (2003), see 174763.0007. </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>.0013 SENSORY ATAXIC NEUROPATHY, DYSARTHRIA, AND OPHTHALMOPARESIS</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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SPINOCEREBELLAR ATAXIA WITH EPILEPSY, INCLUDED<br />
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MITOCHONDRIAL DNA DEPLETION SYNDROME 4A (ALPERS TYPE), INCLUDED
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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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POLG, TRP748SER ({dbSNP rs113994097})
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<br />
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SNP: rs113994097,
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gnomAD: rs113994097,
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ClinVar: RCV000014459, RCV000014460, RCV000014461, RCV000080023, RCV000144870, RCV000313739, RCV000507757, RCV000508846, RCV001198081, RCV002247336, RCV002313710, RCV003985719, RCV005007848
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</span>
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</div>
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<div>
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|
<span class="mim-text-font">
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|
<p>In 3 Finnish sibs with sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO; 607459), previously reported by Rantamaki et al. (2001), Van Goethem et al. (2004) identified a homozygous 2243G-C transversion in the POLG gene, resulting in a trp748-to-ser (W748S) substitution. The mutated residue lies within a highly conserved block of 6 amino acids that form a beta-sheet in the spacer, or linker, region of the enzyme and is presumed to be involved in primer-template interaction of the DNA polymerase. An unrelated Finnish patient had the same homozygous mutation, and an unrelated British patient was compound heterozygous for W748S and A467T (174763.0002). In addition to the W748S mutation, all 5 patients carried a 3428A-G transition, resulting in a glu1143-to-gly (E1143G) substitution on the same allele. W748S was not identified in 168 Belgian and 70 Finnish controls; E1143G was identified in 11 Belgian and 3 Finnish controls. Van Goethem et al. (2004) concluded that E1143G is a low-frequency polymorphism that forms a common ancestral haplotype; however, they noted that the contribution of E1143G to the phenotype was unclear. </p><p>In a follow-up on the family reported by Rantamaki et al. (2001) and Van Goethem et al. (2004), Rantamaki et al. (2007) found that heterozygous W748S carriers showed no clinically manifesting phenotype. Presumably unrelated neurologic signs and symptoms, including dementia, epilepsy, and migraine, were found in several carriers, but clearly defined neurologic diseases did not segregate with the mutation. The only notable finding was a subclinical axonal sensory neuropathy in the majority of carriers. </p><p>Hakonen et al. (2005) found that the POLG allele with W748S and E1143G in cis is among the most common genetic causes of inherited ataxia in Finland. They identified 27 patients with mitochondrial recessive ataxia syndrome from 15 Finnish families, with a carrier frequency in the general population of 1:125. Since the mutation pair W748S+E1143G has also been described in European patients, they examined the haplotypes of 13 non-Finnish European patients with the W748S mutation. Haplotype analysis demonstrated that all the chromosomes carrying these 2 changes, in patients from Finland, Norway, the United Kingdom, and Belgium, originate from a common ancient founder. In Finland and Norway, long, common Northern haplotypes outside the core haplotype could be identified. Despite having identical homozygous mutations, the Finnish patients with this adult- or juvenile-onset disease had surprisingly heterogeneous phenotypes, albeit with a characteristic set of features, including ataxia, peripheral neuropathy, dysarthria, mild cognitive impairment, involuntary movements, psychiatric symptoms, and epileptic seizures. The high carrier frequency in Finland, the high number of patients in Norway, and the ancient European founder chromosome indicated that this form of ataxia should be considered in the first-line differential diagnosis of progressive ataxia syndromes. </p><p>Winterthun et al. (2005) identified a homozygous W748S mutation in affected members from 2 families with a form of SANDO characterized by early onset of migraine headaches and/or seizures, and the later development of myoclonus (see SCAE; 607459). Both patients were also homozygous for another putative disease-causing POLG mutation (Q497H; 174763.0016). </p><p>In 4 children with mitochondrial DNA depletion syndrome-4A (203700), manifest as Alpers syndrome, Davidzon et al. (2005) identified compound heterozygosity for 2 mutations in the POLG gene: W748S and G848S (174763.0006). All patients died in childhood. Nguyen et al. (2005) reported a patient with Alpers syndrome who was compound heterozygous for G848S and W748S. </p><p>Hakonen et al. (2007) demonstrated that the disease W748S haplotype in patients from Australia and New Zealand derived from a common European haplotype. This haplotype shared a long region with the Finnish and Norwegian haplotype, but differed from Belgian and British patients, suggesting that the founder who formed the isolate in Australia and New Zealand may have been of Scandinavian rather than British origin. Hakonen et al. (2007) estimated that the common ancestor for the W748S haplotype lived more than 40 to 60 generations ago, before 1200 to 800 A.D. </p>
|
|
</span>
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</div>
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<div>
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<br />
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|
</div>
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</div>
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|
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<div>
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|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
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|
|
|
POLG, ALA957SER
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<br />
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|
|
SNP: rs121918051,
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|
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|
|
gnomAD: rs121918051,
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|
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ClinVar: RCV000014462, RCV003460472
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|
|
|
|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of 2 families, originating from a small village in northwest Sicily, with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions (PEOA1; 157640), Lamantea et al. (2002) identified a heterozygous 2869G-T transversion in the POLG gene, resulting in an ala957-to-ser (A957S) substitution. One patient in 1 of the families was homozygous for the A957S mutation and showed a more severe phenotype with earlier onset and a much higher amount of mtDNA deletions than his mildly affected heterozygous mother. Microsatellite analysis showed a common disease haplotype, supporting a common origin in these 2 families. </p>
|
|
</span>
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</div>
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<div>
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|
<br />
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|
</div>
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|
</div>
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<div>
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|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLG, TYR831CYS
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|
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|
<br />
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|
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SNP: rs41549716,
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|
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gnomAD: rs41549716,
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|
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|
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ClinVar: RCV000014463, RCV000175036, RCV000224425, RCV000464026, RCV001117866, RCV001847604, RCV002313711, RCV003985720
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant, formerly titled PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 1, has been reclassified as a variant of unknown significance based on the findings of Luoma et al. (2007). </p><p>In 2 sibs with early-onset parkinsonism and PEOA1 (157640), Mancuso et al. (2004) identified a heterozygous 2492A-G transition in exon 16 of the POLG gene, resulting in a tyr831-to-cys (Y831C) substitution. Parkinsonism was a prominent feature in both patients. </p><p>Luoma et al. (2007) identified the Y831C substitution in 5 controls, suggesting that it is a polymorphism. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 SPINOCEREBELLAR ATAXIA WITH EPILEPSY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLG, GLN497HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918052,
|
|
|
|
|
|
gnomAD: rs121918052,
|
|
|
|
|
|
ClinVar: RCV000014464, RCV000144870, RCV000528996, RCV000676325, RCV002496360, RCV003230363
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members from 2 families with a form of SANDO characterized by early onset of migraine headaches and/or seizures, and the later development of myoclonus (see SCAE; 607459), Winterthun et al. (2005) identified a homozygous 1491G-C transversion in the POLG gene, resulting in a gln497-to-his (Q497H) substitution. Both patients were also homozygous for another disease-causing POLG mutation (W748S; 174763.0013). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
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|
|
</div>
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|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 MITOCHONDRIAL DNA DEPLETION SYNDROME 4A (ALPERS TYPE)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLG, TRP1020TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1567185775,
|
|
|
|
|
|
|
|
ClinVar: RCV000014465
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sisters with mitochondrial DNA depletion syndrome-4A (MTDPS4A; 203700), manifest as Alpers syndrome, Nguyen et al. (2005) identified compound heterozygosity for 2 mutations in the POLG gene: a 3339G-A transition in exon 19, resulting in a trp1020-to-ter (W1020X) substitution, and A467T (174763.0002). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLG, ARG853TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918053,
|
|
|
|
|
|
gnomAD: rs121918053,
|
|
|
|
|
|
ClinVar: RCV000014466, RCV000560575, RCV001449754, RCV003330388, RCV003333951, RCV005007849
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 Italian sisters with early-onset parkinsonism, peripheral sensory neuropathy, and mitochondrial DNA deletions but without PEO (PEOB1; 258450), Davidzon et al. (2006) identified compound heterozygosity for 2 mutations in the POLG gene: a 2839C-T transition in exon 16 resulting in an arg853-to-trp (R853W) substitution and a 2491G-C transversion in exon 13 resulting in a gly737-to-arg (G737R; 174763.0019) substitution. The R853W and G737R substitutions occurred in the polymerase domain and the linker region, respectively. Each unaffected parent was heterozygous for 1 of the mutations. Despite the absence of PEO, the phenotype was most consistent with the clinical features of that disorder. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLG, GLY737ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918054,
|
|
|
|
|
|
gnomAD: rs121918054,
|
|
|
|
|
|
ClinVar: RCV000014467, RCV000188568, RCV000233045, RCV000370280, RCV000508744, RCV000768053, RCV001004601, RCV001813987, RCV001847605, RCV002316196, RCV003318542, RCV003985721
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the gly737-to-arg (G737R) mutation in the POLG gene that was found in compound heterozygous state in 2 Italian sisters with autosomal recessive progressive external ophthalmopletia with mitochondrial DNA deletions (PEOB1; 258450) by Davidzon et al. (2006), see 174763.0018. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLG, SER511ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918055,
|
|
|
|
|
|
|
|
ClinVar: RCV000014468
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 6 affected members of a large family with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions (PEOA1; 157640), Hudson et al. (2007) identified a heterozygous 1532G-A transition in exon 8 of the POLG gene, resulting in a ser511-to-asn (S511N) substitution in the linker region of the protein. The substitution was not identified in 192 control chromosomes or 248 disease control subjects. The S511N pathogenic mutation was found on the same allele as an intronic variant (2070+158G-A), which the authors considered unlikely to have functional consequences. All patients had ptosis, and 1 had external ophthalmoplegia. The 69-year-old asymptomatic sister of the index patient also carried the S511N mutation, suggesting incomplete penetrance. The female index patient had ataxia, hearing loss, and sensory axonal neuropathy. Her son also had hearing loss and parkinsonism and was found to have a second POLG variant (1389G-A) on the other allele, but both his carrier sister and obligate carrier father had no reported neurologic abnormalities. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 MITOCHONDRIAL DNA DEPLETION SYNDROME 4B (MNGIE TYPE)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLG, ARG227TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918056,
|
|
|
|
|
|
gnomAD: rs121918056,
|
|
|
|
|
|
ClinVar: RCV000014469, RCV000255169, RCV000525480, RCV000787362, RCV002513044, RCV004586007, RCV005007850
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the arg227-to-trp (R227W) mutation in the POLG gene that was found in compound heterozygous state in an infant with mtDNA depletion syndrome-4B (MTDPS4B; 613662) by Giordano et al. (2009), see 174763.0006. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 MITOCHONDRIAL DNA DEPLETION SYNDROME 4A (ALPERS TYPE)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
MITOCHONDRIAL DNA DEPLETION SYNDROME 4B (MNGIE TYPE), INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLG, PRO1073LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267606959,
|
|
|
|
|
|
gnomAD: rs267606959,
|
|
|
|
|
|
ClinVar: RCV000014470, RCV000014471, RCV000188673
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
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|
<p>Kurt et al. (2010) identified a 3218C-T transition in exon 20 of the POLG gene, resulting in a pro1073-to-leu (P1073L) substitution, in compound heterozygosity with another pathogenic POLG mutation in 4 patients who all had a hepatocerebral disorder with psychomotor delay, seizures, and liver disease, consistent with mitochondrial DNA depletion syndrome-4A (MTDPS4A; 203700), manifest as Alpers syndrome. The P1073L mutation occurred in a conserved residue in the polymerase domain of the protein. An unrelated girl and boy were compound heterozygous for the P1073L and A467T (174763.0002) mutations. Both had developmental delay. The girl was hypotonic at birth, and later had short stature, neurosensory hearing loss, celiac disease, liver dysfunction with hepatic fibrosis, and gastrointestinal pseudoobstruction with dysmotility, reminiscent of the allelic disorder MNGIE syndrome (MTDPS4B; 613662). Brain MRI showed signal abnormalities in the basal ganglia and thalami. She died at age 9 years. RT-PCR showed severe mtDNA depletion in liver tissue (72.1% depletion compared to controls). The boy had status epilepticus with coma, cholestasis, optic atrophy, hyperplastic gastropathy with gastric ulcer, and death at age 3 years, 4 months. In addition, 2 boys were compound heterozygous for the P1073L and W748S (174763.0013) and G848S (174763.0006) mutations, respectively. The first child had severe attention-deficit/hyperactivity disorder with motor and verbal tics, status epilepticus with coma and myoclonus, liver dysfunction, and cavitation in the cerebrum, thalamus, cerebellum, and basal ganglia. He died at age 13 years. The other child had poor growth, hypotonia, seizures, and intestinal hypomotility and died at age 10 months. Muscle tissue showed mtDNA depletion (64%). Kurt et al. (2010) emphasized the phenotypic variability associated with POLG mutations, and noted that various signs and symptoms can occur in each associated disorder. Three of the children with the P1073L mutation also had gastrointestinal dysmotility, suggesting that this mutation may be associated with that particular feature. </p>
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Walker, R. L., Anziano, P., Meltzer, P. S.
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<strong>A PAC containing the human mitochondrial DNA polymerase gamma gene (POLG) maps to chromosome 15q25.</strong>
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Winterthun, S., Ferrari, G., He, L., Taylor, R. W., Zeviani, M., Turnbull, D. M., Engelsen, B. A., Moen, G., Bindoff, L. A.
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Zullo, S. J., Butler, L., Zahorchak, R. J., Macville, M., Wilkes, C., Merril, C. R.
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<strong>Localization by fluorescence in situ hybridization (FISH) of human mitochondrial polymerase gamma (POLG) to human chromosome band 15q24-q26, and of mouse mitochondrial polymerase gamma (Polg) to mouse chromosome band 7E, with confirmation by direct sequence analysis of bacterial artificial chromosomes (BACs).</strong>
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Hilary J. Vernon - updated : 08/14/2024<br>Matthew B. Gross - updated : 03/18/2024<br>Bao Lige - updated : 03/14/2024<br>Cassandra L. Kniffin - updated : 10/10/2016<br>Cassandra L. Kniffin - updated : 3/23/2016<br>Ada Hamosh - updated : 10/25/2013<br>George E. Tiller - updated : 8/21/2013<br>Cassandra L. Kniffin - updated : 10/26/2011<br>Cassandra L. Kniffin - updated : 12/10/2010<br>Cassandra L. Kniffin - updated : 5/11/2010<br>Cassandra L. Kniffin - updated : 8/27/2009<br>Cassandra L. Kniffin - updated : 7/9/2009<br>Cassandra L. Kniffin - updated : 6/1/2009<br>George E. Tiller - updated : 11/14/2008<br>George E. Tiller - updated : 10/28/2008<br>Patricia A. Hartz - updated : 9/24/2008<br>Ada Hamosh - updated : 4/23/2008<br>Cassandra L. Kniffin - updated : 1/29/2008<br>Cassandra L. Kniffin - updated : 12/27/2007<br>Cassandra L. Kniffin - updated : 12/14/2007<br>Cassandra L. Kniffin - updated : 10/1/2007<br>Cassandra L. Kniffin - updated : 9/12/2007<br>Cassandra L. Kniffin - updated : 2/15/2007<br>Cassandra L. Kniffin - updated : 6/20/2006<br>Ada Hamosh - updated : 11/14/2005<br>Cassandra L. Kniffin - updated : 10/13/2005<br>Cassandra L. Kniffin - updated : 8/31/2005<br>Victor A. McKusick - updated : 8/18/2005<br>Ada Hamosh - updated : 8/15/2005<br>Cassandra L. Kniffin - updated : 6/9/2005<br>Victor A. McKusick - updated : 4/26/2005<br>John A. Phillips, III - updated : 4/25/2005<br>Cassandra L. Kniffin - updated : 3/30/2005<br>Cassandra L. Kniffin - updated : 2/21/2005<br>Marla J. F. O'Neill - updated : 11/4/2004<br>Cassandra L. Kniffin - updated : 8/31/2004<br>Ada Hamosh - updated : 7/22/2004<br>Cassandra L. Kniffin - updated : 1/9/2004<br>Victor A. McKusick - updated : 7/21/2003<br>Cassandra L. Kniffin - updated : 6/20/2003<br>Victor A. McKusick - updated : 10/19/2001<br>Ada Hamosh - updated : 6/28/2001<br>Rebekah S. Rasooly - updated : 4/7/1998<br>Victor A. McKusick - updated : 3/16/1998
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Victor A. McKusick : 1/3/1991
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