5298 lines
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Entry
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- *606075 - TWINKLE mtDNA HELICASE; TWNK
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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">*606075</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/606075">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</div>
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</div>
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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="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=ENSG00000107815;t=ENST00000311916" 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=56652" 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=606075" 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 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=ENSG00000107815;t=ENST00000311916" 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_001163812,NM_001163813,NM_001163814,NM_001368275,NM_021830,NR_160738,NR_160739,NR_160740,NR_160741,NR_160742" 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_021830" 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=606075" 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=05830&isoform_id=05830_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/TWNK" 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/10438015,14582616,14582618,21707100,34365099,39644620,39725942,74752111,119570178,119570179,170560895,194386050,255304946,255304948,255304960,311349658,311349660,311349662,311349664,311349666,311349668,311349670,311349672,311349674,311349676,311349678,311349680,311349682,311349684,311349686,311349688,311349690,311349692,311349694,311349696,311349698,311349700,311349702,311349704,311349706,311349708,311349710,311349712,311349714,311349716,311349718,311349720,311349722,311349724,311349726,311349728,311349730,311349732,311349734,311349736,1566185456" 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/Q96RR1" 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=56652" 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=ENSG00000107815;t=ENST00000311916" 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=TWNK" 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=TWNK" 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+56652" 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/TWNK" 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:56652" 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/56652" 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=chr10&hgg_gene=ENST00000311916.8&hgg_start=100987543&hgg_end=100994403&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://medlineplus.gov/genetics/gene/twnk" 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=606075[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=606075[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000107815" 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=TWNK" 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=TWNK" 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=TWNK" 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=TWNK&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/PA162377675" 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:1160" 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/FBgn0032154.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:2137410" 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/TWNK#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:2137410" 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/56652/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=56652" 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=WBGene00018514;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-030131-5569" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<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:56652" 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=TWNK&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> 724227000<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">
|
|
<span class="text-danger"><strong>*</strong></span>
|
|
606075
|
|
</span>
|
|
</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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TWINKLE mtDNA HELICASE; TWNK
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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">
|
|
CHROMOSOME 10 OPEN READING FRAME 2; C10ORF2<br />
|
|
T7 GENE 4-LIKE PROTEIN WITH INTRAMITOCHONDRIAL NUCLEOID LOCALIZATION; TWINKLE<br />
|
|
p72
|
|
</span>
|
|
</h4>
|
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</div>
|
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</div>
|
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<div>
|
|
<br />
|
|
</div>
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<div>
|
|
<a id="includedTitles" class="mim-anchor"></a>
|
|
<div>
|
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<p>
|
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<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
TWINKY, INCLUDED
|
|
</span>
|
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</div>
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</div>
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<div>
|
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<br />
|
|
</div>
|
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=TWNK" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TWNK</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/10/489?start=-3&limit=10&highlight=489">10q24.31</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr10:100987543-100994403&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'})">10:100,987,543-100,994,403</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
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|
|
</span>
|
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</p>
|
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</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>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=271245,616138,609286" 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="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/10/489?start=-3&limit=10&highlight=489">
|
|
10q24.31
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Mitochondrial DNA depletion syndrome 7 (hepatocerebral type)
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/271245"> 271245 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
|
</span>
|
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</td>
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</tr>
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<tr>
|
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<td>
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<p>The TWNK gene encodes a mitochondrial protein with structural similarity to the phage T7 primase/helicase (GP4) and other hexameric ring helicases. The twinkle protein colocalizes with mtDNA in mitochondrial nucleoids, and its name derives from the unusual localization pattern reminiscent of twinkling stars (summary by <a href="#16" class="mim-tip-reference" title="Spelbrink, J. N., Li, F.-Y., Tiranti, V., Nikali, K., Yuan, Q.-P., Tariq, M., Wanrooij, S., Garrido, N., Comi, G., Morandi, L., Santoro, L., Toscano, A., and 9 others. <strong>Human mitochondrial DNA deletions associated with mutations in the gene encoding twinkle, a phage T7 gene 4-like protein localized in mitochondria.</strong> Nature Genet. 28: 223-231, 2001. Note: Erratum: Nature Genet. 29: 100 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431692</a>] [<a href="https://doi.org/10.1038/90058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431692">Spelbrink et al., 2001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11431692" 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="#16" class="mim-tip-reference" title="Spelbrink, J. N., Li, F.-Y., Tiranti, V., Nikali, K., Yuan, Q.-P., Tariq, M., Wanrooij, S., Garrido, N., Comi, G., Morandi, L., Santoro, L., Toscano, A., and 9 others. <strong>Human mitochondrial DNA deletions associated with mutations in the gene encoding twinkle, a phage T7 gene 4-like protein localized in mitochondria.</strong> Nature Genet. 28: 223-231, 2001. Note: Erratum: Nature Genet. 29: 100 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431692</a>] [<a href="https://doi.org/10.1038/90058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431692">Spelbrink et al. (2001)</a> identified the C10ORF2 gene, which encodes a protein similar to T7 GP4, by searching for open reading frames (ORFs) in a region linked to PEOA3 (<a href="/entry/609286">609286</a>) on 10q24. C10ORF2 has a mitochondrial targeting sequence at the N terminus. The predicted full-length protein, which the authors designated twinkle, has 684 amino acids with a molecular mass of 77 kD. <a href="#16" class="mim-tip-reference" title="Spelbrink, J. N., Li, F.-Y., Tiranti, V., Nikali, K., Yuan, Q.-P., Tariq, M., Wanrooij, S., Garrido, N., Comi, G., Morandi, L., Santoro, L., Toscano, A., and 9 others. <strong>Human mitochondrial DNA deletions associated with mutations in the gene encoding twinkle, a phage T7 gene 4-like protein localized in mitochondria.</strong> Nature Genet. 28: 223-231, 2001. Note: Erratum: Nature Genet. 29: 100 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431692</a>] [<a href="https://doi.org/10.1038/90058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431692">Spelbrink et al. (2001)</a> identified a splice variant resulting from the use of a downstream exon 4 splice donor site that leads to a 43-bp insertion between the regular exon 4-exon 5 sequence. The protein encoded by the variant mRNA, which the authors called twinky, has a molecular mass of 66 kD and has 582 amino acids; it lacks residues 579 through 684 and terminates with 4 unique amino acids. Both cDNA variants, when expressed transiently in HEK293T cells, directed the synthesis of proteins close to the expected molecular masses. The authors found that C. elegans and Drosophila have similar proteins, also related to T7 GP4. S. pombe has a few homologs with low similarity, but <a href="#16" class="mim-tip-reference" title="Spelbrink, J. N., Li, F.-Y., Tiranti, V., Nikali, K., Yuan, Q.-P., Tariq, M., Wanrooij, S., Garrido, N., Comi, G., Morandi, L., Santoro, L., Toscano, A., and 9 others. <strong>Human mitochondrial DNA deletions associated with mutations in the gene encoding twinkle, a phage T7 gene 4-like protein localized in mitochondria.</strong> Nature Genet. 28: 223-231, 2001. Note: Erratum: Nature Genet. 29: 100 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431692</a>] [<a href="https://doi.org/10.1038/90058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431692">Spelbrink et al. (2001)</a> could not identify a related sequence in S. cerevisiae. Multiple sequence alignment of the various proteins showed greatest similarity in the domain responsible for helicase activity in the phage T7 protein, which is located in its C terminus. The degree of identity between the human and a partial mouse sequence is approximately 85%, whereas the identity between the mammalian and vertebrate sequences is 35 to 40%. Northern blot analysis detected full-length mRNAs of 4 kb, significantly larger than the 2.1-kb ORF. Twinkle was expressed at high relative levels in skeletal muscle and pancreas and at low levels in heart. The relative level of twinkle expression in skeletal muscle was probably underestimated because of the strong crossreacting alpha-actin mRNA species just below the beta-actin mRNA. Twinkle is localized to mitochondrial nucleoids and shows an unusual localization pattern reminiscent of twinkling stars. Cells overexpressing twinkle had a modestly increased mtDNA helicase activity. The function of twinkle was presumed to be critical for lifetime maintenance of human mitochondrial integrity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11431692" 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="#22" class="mim-tip-reference" title="Van Hove, J. L. K., Cunningham, V., Rice, C., Ringel, S. P., Zhang, Q., Chou, P.-C., Truong, C. K., Wong, L.-J. C. <strong>Finding twinkle in the eyes of a 71-year-old lady: A case report and review of the genotypic and phenotypic spectrum of TWINKLE-related dominant disease.</strong> Am. J. Med. Genet. 149A: 861-867, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19353676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19353676</a>] [<a href="https://doi.org/10.1002/ajmg.a.32731" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19353676">Van Hove et al. (2009)</a> noted that the twinkle protein contains 3 functional domains: a 3-prime helicase region, required for mtDNA replication, a linker region involved in oligomerization into a hexamer required for helicase activity, and a 5-primase domain. Most pathogenic mutations occur in the helicase or linker regions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19353676" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#3" class="mim-tip-reference" title="Farge, G., Holmlund, T., Khvorostova, J., Rofougaran, R., Hofer, A., Falkenberg, M. <strong>The N-terminal domain of TWINKLE contributes to single-stranded DNA binding and DNA helicase activities.</strong> Nucleic Acids Res. 36: 393-403, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18039713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18039713</a>] [<a href="https://doi.org/10.1093/nar/gkm1025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18039713">Farge et al. (2008)</a> showed that purified recombinant human TWINKLE formed hexamers, even in the absence of Mg(2+) or ATP, at high ionic strength. The C-terminal domain of TWINKLE was essential for hexamer formation, but the N-terminal domain also contributed to proper hexamerization. TWINKLE interacted with both single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA), preferably with long ssDNA or dsDNA. The C-terminal helicase domain of TWINKLE was responsible for DNA binding, but the N-terminal domain specifically contributed to ssDNA-binding activity. ssDNA stimulated the intrinsic ATPase activity of TWINKLE. The N-terminal region of TWINKLE was not absolutely required for its ATPase activity, but it had a positive effect on levels of ATPase activity, as well as ssDNA-dependent stimulation, helicase activity, and DNA synthesis on a duplex DNA template. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18039713" 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 recombinant protein expressed in E. coli, <a href="#10" class="mim-tip-reference" title="Longley, M. J., Humble, M. M., Sharief, F. S., Copeland, W. C. <strong>Disease variants of the human mitochondrial DNA helicase encoded by C10orf2 differentially alter protein stability, nucleotide hydrolysis, and helicase activity.</strong> J. Biol. Chem. 285: 29690-29702, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20659899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20659899</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20659899[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/10.1074/jbc.M110.151795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20659899">Longley et al. (2010)</a> showed that human C10ORF2, which they called p72, bound both ssDNA and dsDNA, catalyzed DNA unwinding, and required ATP and Mg(2+) for helicase activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20659899" 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="Sen, D., Nandakumar, D., Tang, G.-Q., Patel, S. S. <strong>Human mitochondrial DNA helicase TWINKLE is both an unwinding and annealing helicase.</strong> J. Biol. Chem. 287: 14545-14556, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22383523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22383523</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22383523[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/10.1074/jbc.M111.309468" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22383523">Sen et al. (2012)</a> showed that recombinant human twinkle formed oligomers spontaneously, but that it formed hexamers specifically in the presence of MgUTP, which appeared to stabilize the hexameric state. Twinkle bound both ssDNA and dsDNA via different binding sites with distinct binding affinities. DNA binding was independent of Mg(2+) or nucleotide triphosphates (NTP). Twinkle showed unwinding activity predominantly with 5-prime-tailed dsDNA substrates in the presence of several NTPs and Mg(2+), and it required its NTPase activity for dsDNA unwinding. Unwinding of dsDNA was facilitated by inclusion of T7 gp2.5 single strand-binding protein or complementary ssDNA to prevent reannealing of the unwound displaced strand. Twinkle also showed UTP-independent DNA annealing of 2 ssDNA strands in the absence of gp2.5 or complementary ssDNA. <a href="#15" class="mim-tip-reference" title="Sen, D., Nandakumar, D., Tang, G.-Q., Patel, S. S. <strong>Human mitochondrial DNA helicase TWINKLE is both an unwinding and annealing helicase.</strong> J. Biol. Chem. 287: 14545-14556, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22383523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22383523</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22383523[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/10.1074/jbc.M111.309468" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22383523">Sen et al. (2012)</a> concluded that twinkle is a bifunctional helicase with both unwinding and annealing activities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22383523" 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>TWINKLE comprises a DNA helicase domain and a primase domain joined by a flexible linker helix. Using negative stain analysis, <a href="#13" class="mim-tip-reference" title="Peter, B., Farge, G., Pardo-Hernandez, C., Tangefjord, S., Falkenberg, M. <strong>Structural basis for adPEO-causing mutations in the mitochondrial TWINKLE helicase.</strong> Hum. Molec. Genet. 28: 1090-1099, 2019. Note: Erratum: Hum. Molec. Genet. 29: 528 only, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30496414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30496414</a>] [<a href="https://doi.org/10.1093/hmg/ddy415" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30496414">Peter et al. (2019)</a> showed that TWINKLE was present as a mixture of hexameric and heptameric species. These oligomers formed star-like structures with the helicase domain forming an internal ring and the primase domain extending into the solvent. TWINKLE underwent conformational changes in the presence of nucleotides, leading to structural compaction and repositioning of the primase domain and the formation of hexamers and heptamers with smaller diameters. The linker helix contacted the neighboring helicase domain, connecting 1 monomer to the next. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30496414" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions, Autosomal Dominant, 3</em></strong></p><p>
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In a Finnish family and a Pakistani family with autosomal dominant progressive external ophthalmoplegia (PEOA3; <a href="/entry/609286">609286</a>), <a href="#16" class="mim-tip-reference" title="Spelbrink, J. N., Li, F.-Y., Tiranti, V., Nikali, K., Yuan, Q.-P., Tariq, M., Wanrooij, S., Garrido, N., Comi, G., Morandi, L., Santoro, L., Toscano, A., and 9 others. <strong>Human mitochondrial DNA deletions associated with mutations in the gene encoding twinkle, a phage T7 gene 4-like protein localized in mitochondria.</strong> Nature Genet. 28: 223-231, 2001. Note: Erratum: Nature Genet. 29: 100 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431692</a>] [<a href="https://doi.org/10.1038/90058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431692">Spelbrink et al. (2001)</a> identified 2 different heterozygous mutations in the C10ORF2 gene (<a href="#0001">606075.0001</a> and <a href="#0002">606075.0002</a>, respectively). Nine additional heterozygous mutations in the C10ORF2 gene (see, e.g., <a href="#0003">606075.0003</a>-<a href="#0007">606075.0007</a>) were identified in 9 unrelated Italian PEO families and 1 British PEO family out of over 70 PEO families tested. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11431692" 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>One of the mutations identified by <a href="#16" class="mim-tip-reference" title="Spelbrink, J. N., Li, F.-Y., Tiranti, V., Nikali, K., Yuan, Q.-P., Tariq, M., Wanrooij, S., Garrido, N., Comi, G., Morandi, L., Santoro, L., Toscano, A., and 9 others. <strong>Human mitochondrial DNA deletions associated with mutations in the gene encoding twinkle, a phage T7 gene 4-like protein localized in mitochondria.</strong> Nature Genet. 28: 223-231, 2001. Note: Erratum: Nature Genet. 29: 100 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431692</a>] [<a href="https://doi.org/10.1038/90058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431692">Spelbrink et al. (2001)</a> was a val368-to-ile (V368I) change, found in 2 Sicilian families with PEO. However, <a href="#1" class="mim-tip-reference" title="Arenas, J., Briem, E., Dahl, H., Hutchison, W., Lewis, S., Martin, M. A., Spelbrink, H., Tiranti, V., Jacobs, H., Zeviani, M. <strong>The V368I mutation in twinkle does not segregate with adPEO. (Letter)</strong> Ann. Neurol. 53: 278 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12557300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12557300</a>] [<a href="https://doi.org/10.1002/ana.10430" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12557300">Arenas et al. (2003)</a> reported that they found the same change in 1.2% of a normal control population and concluded that the change is a nonpathogenic polymorphism. A proband from 1 of the families with the mutation was later found to have mutations in the POLG gene (<a href="/entry/174763">174763</a>), which was presumably the disease-causing gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12557300+11431692" 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 sporadic PEO, <a href="#21" 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 arg334-to-gln substitution in the C10ORF2 gene (R334Q; <a href="#0008">606075.0008</a>) cooccurring with a heterozygous gly848-to-ser mutation in the POLG gene (G848S; <a href="/entry/174763#0006">174763.0006</a>). Both mutations were absent in 180 Belgian control chromosomes. No mutations were found in the ANT1 gene (SLC25A4; <a href="/entry/103220">103220</a>). <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 5 patients from 2 unrelated French families with autosomal dominant PEOA3, <a href="#2" class="mim-tip-reference" title="Echaniz-Laguna, A., Chanson, J. B., Wilhelm, J. M., Sellal, F., Mayencon, M., Mohr, M., Tranchant, C., de Camaret, B. M. <strong>A novel variation in the Twinkle linker region causing late-onset dementia.</strong> Neurogenetics 11: 21-25, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19513767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19513767</a>] [<a href="https://doi.org/10.1007/s10048-009-0202-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19513767">Echaniz-Laguna et al. (2010)</a> identified a heterozygous mutation in the C10ORF2 gene (R374W; <a href="#0014">606075.0014</a>). Common features included ptosis, ophthalmoplegia, hearing loss, sensory axonal neuropathy, and proximal muscle weakness. The older patients, including deceased affected family members, developed abnormal gait, dysphagia, dysphonia, and late-onset dementia in their seventies and eighties. The findings expanded the phenotypic spectrum of PEOA3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19513767" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Autosomal Recessive Mitochondrial DNA Depletion Syndrome 7 (Hepatocerebral Type)</em></strong></p><p>
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In Finnish patients with autosomal recessive mitochondrial DNA depletion syndrome-7 (MTDPS7; <a href="/entry/271245">271245</a>), manifest as infantile-onset spinocerebellar ataxia (IOSCA), <a href="#12" class="mim-tip-reference" title="Nikali, K., Suomalainen, A., Saharinen, J., Kuokkanen, M., Spelbrink, J. N., Lonnqvist, T., Peltonen, L. <strong>Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins twinkle and twinky.</strong> Hum. Molec. Genet. 14: 2981-2990, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16135556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16135556</a>] [<a href="https://doi.org/10.1093/hmg/ddi328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16135556">Nikali et al. (2005)</a> identified homozygosity for a founder mutation in the C10ORF2 gene, Y508C (<a href="#0012">606075.0012</a>). The phenotype was a severe neurodegenerative disorder characterized by progressive atrophy of the cerebellum, brainstem, and spinal cord and sensory axonal neuropathy, <a href="#5" class="mim-tip-reference" title="Hakonen, A. H., Goffart, S., Marjavaara, S., Paetau, A., Cooper, H., Mattila, K., Lampinen, M., Sajantila, A., Lonnqvist, T., Spelbrink, J. N., Suomalainen, A. <strong>Infantile-onset spinocerebellar ataxia and mitochondrial recessive ataxia syndrome are associated with neuronal complex I defect and mtDNA depletion.</strong> Hum. Molec. Genet. 17: 3822-3835, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18775955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18775955</a>] [<a href="https://doi.org/10.1093/hmg/ddn280" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18775955">Hakonen et al. (2008)</a> found that patients with the Y508C mutation had mtDNA depletion in brain tissue and liver. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18775955+16135556" 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 Algerian sibs and a first cousin with autosomal recessive mitochondrial DNA deletion syndrome-7, <a href="#14" class="mim-tip-reference" title="Sarzi, E., Goffart, S., Serre, V., Chretien, D., Slama, A., Munnich, A., Spelbrink, J. N., Rotig, A. <strong>Twinkle helicase (PEO1) gene mutation causes mitochondrial DNA depletion.</strong> Ann. Neurol. 62: 579-587, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17722119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17722119</a>] [<a href="https://doi.org/10.1002/ana.21207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17722119">Sarzi et al. (2007)</a> identified a homozygous mutation in the C10ORF2 gene (<a href="#0011">606075.0011</a>). All 3 patients were born of first-cousin parents and showed a severe hepatocerebral phenotype characterized by neonatal hypotonia, mild liver insufficiency, increased serum and CSF lactate, psychomotor retardation, seizures, and peripheral neuropathy. All 3 patients died by age 3 years. Mitochondrial DNA depletion was severe in 2 patients examined, with mtDNA levels in liver of 8% and 5% of normal, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17722119" 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>Perrault Syndrome 5</em></strong></p><p>
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In 4 women from 2 unrelated families with Perrault syndrome-5 (PRLTS5; <a href="/entry/616138">616138</a>), <a href="#11" class="mim-tip-reference" title="Morino, H., Pierce, S. B., Matsuda, Y., Walsh, T., Ohsawa, R., Newby, M., Hiraki-Kamon, K., Kuramochi, M., Lee, M. K., Klevit, R. E., Martin, A., Maruyama, H., King, M.-C., Kawakami, H. <strong>Mutations in Twinkle primase-helicase cause Perrault syndrome with neurologic features.</strong> Neurology 83: 2054-2061, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25355836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25355836</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25355836[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/10.1212/WNL.0000000000001036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25355836">Morino et al. (2014)</a> identified compound heterozygous mutations in the C10ORF2 gene (<a href="#0016">606075.0016</a>-<a href="#0019">606075.0019</a>). The mutations, which were found by exome sequencing, segregated with the disorder in the families. All 4 mutations occurred in the helicase domain and were predicted to adversely affect enzyme activity based on structure, but functional studies of the variants were not performed. The patients presented as teenagers with primary amenorrhea and sensorineural hearing loss, and later developed ataxia and sensory axonal neuropathy. <a href="#11" class="mim-tip-reference" title="Morino, H., Pierce, S. B., Matsuda, Y., Walsh, T., Ohsawa, R., Newby, M., Hiraki-Kamon, K., Kuramochi, M., Lee, M. K., Klevit, R. E., Martin, A., Maruyama, H., King, M.-C., Kawakami, H. <strong>Mutations in Twinkle primase-helicase cause Perrault syndrome with neurologic features.</strong> Neurology 83: 2054-2061, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25355836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25355836</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25355836[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/10.1212/WNL.0000000000001036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25355836">Morino et al. (2014)</a> noted that the report expanded the phenotypic spectrum associated with recessive C10ORF2 mutations to include less severe neurologic involvement compared to MTDPS7 and a clinical presentation consistent with Perrault syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25355836" 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>Functional Studies of Mutant C10ORF2</em></strong></p><p>
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<a href="#10" class="mim-tip-reference" title="Longley, M. J., Humble, M. M., Sharief, F. S., Copeland, W. C. <strong>Disease variants of the human mitochondrial DNA helicase encoded by C10orf2 differentially alter protein stability, nucleotide hydrolysis, and helicase activity.</strong> J. Biol. Chem. 285: 29690-29702, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20659899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20659899</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20659899[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/10.1074/jbc.M110.151795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20659899">Longley et al. (2010)</a> assayed the DNA-binding, DNA-unwinding, and ATPase activities of 20 different human p72 mutants, each containing a different amino acid substitution associated with mitochondrial disease. All 20 mutant forms exhibited helicase activity under the standard reaction conditions. Most substitutions altered DNA binding or the kinetics of ATP hydrolysis or helicase activity of the mutant protein, but none profoundly altered p72 function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20659899" 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="Peter, B., Farge, G., Pardo-Hernandez, C., Tangefjord, S., Falkenberg, M. <strong>Structural basis for adPEO-causing mutations in the mitochondrial TWINKLE helicase.</strong> Hum. Molec. Genet. 28: 1090-1099, 2019. Note: Erratum: Hum. Molec. Genet. 29: 528 only, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30496414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30496414</a>] [<a href="https://doi.org/10.1093/hmg/ddy415" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30496414">Peter et al. (2019)</a> found that TWINKLE with PEOA3-associated mutations in the linker helix could form hexamers and heptamers, albeit at lower levels than wildtype. However, these mutations disrupted subunit flexibility, thereby reducing or eliminating TWINKLE catalytic activity. PEOA3-associated mutations in the TWINKLE primase domain, in close proximity to the primase-linker boundary, targeted the oligomerization process and caused structural and functional changes in TWINKLE. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30496414" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a review of 29 pathogenic mutations in the C10ORF2 gene, <a href="#22" class="mim-tip-reference" title="Van Hove, J. L. K., Cunningham, V., Rice, C., Ringel, S. P., Zhang, Q., Chou, P.-C., Truong, C. K., Wong, L.-J. C. <strong>Finding twinkle in the eyes of a 71-year-old lady: A case report and review of the genotypic and phenotypic spectrum of TWINKLE-related dominant disease.</strong> Am. J. Med. Genet. 149A: 861-867, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19353676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19353676</a>] [<a href="https://doi.org/10.1002/ajmg.a.32731" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19353676">Van Hove et al. (2009)</a> found that all mutations clustered in a short region between residues arg303 and tyr508, involving the primase domains V and VI, the linker region, and the helicase domain. A phenotypic review of 56 patients with these mutations showed that most develop symptoms as adults between age 17 and 73 years. The most common symptoms were progressive external ophthalmoplegia and ptosis (96%). Almost half (46%) had symptoms of myopathy, usually described as limb-girdle, and 14% had a polyneuropathy. Other common features included brainstem symptoms (18%), depression (13%), and parkinsonism or tremors (13%), with less frequent features including diabetes mellitus, ataxia, cataract, memory loss, hearing loss, and cardiac problems. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19353676" 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="#20" class="mim-tip-reference" title="Tyynismaa, H., Sembongi, H., Bokori-Brown, M., Granycome, C., Ashley, N., Poulton, J., Jalanko, A., Spelbrink, J. N., Holt, I. J., Suomalainen, A. <strong>Twinkle helicase is essential for mtDNA maintenance and regulates mtDNA copy number.</strong> Hum. Molec. Genet. 13: 3219-3227, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15509589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15509589</a>] [<a href="https://doi.org/10.1093/hmg/ddh342" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15509589">Tyynismaa et al. (2004)</a> reported that Twinkle expression patterns are not conserved between human and mouse but are synchronized with the adjacent gene Mrpl43, suggesting a shared promoter. The authors generated 2 transgenic mouse lines overexpressing wildtype Twinkle. Increased expression of Twinkle in muscle and heart increased mtDNA copy number up to 3-fold higher than controls, more than any other factor reported to date. In cultured human cells, reduced expression of Twinkle by RNA interference mediated a rapid drop in mtDNA copy number, further supporting the in vivo results. The authors concluded that Twinkle helicase is essential for mtDNA maintenance and that it may be a key regulator of mtDNA copy number in mammals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15509589" 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="#19" class="mim-tip-reference" title="Tyynismaa, H., Mjosund, K. P., Wanrooij, S., Lappalainen, I., Ylikallio, E., Jalanko, A., Spelbrink, J. N., Paetau, A., Suomalainen, A. <strong>Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice.</strong> Proc. Nat. Acad. Sci. 102: 17687-17692, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16301523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16301523</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16301523[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.0505551102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16301523">Tyynismaa et al. (2005)</a> generated transgenic mice overexpressing mouse Twinkle due to mutations corresponding to the PEO-associated mutations ala359 to thr (A359T; <a href="#0003">606075.0003</a>) and duplication of amino acids 352 to 364 (<a href="#0001">606075.0001</a>) in humans. Multiple mtDNA deletions accumulated in the tissues of mutant mice, resulting in progressive respiratory dysfunction and chronic late-onset mitochondrial disease starting at 1 year of age. The muscles of mutant mice faithfully replicated features of PEO patients. These mice had progressive deficiency of cytochrome c oxidase in distinct neuronal populations, but they did not display premature aging. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16301523" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Goffart, S., Cooper, H. M., Tyynismaa, H., Wanrooij, S., Suomalainen, A., Spelbrink, J. N. <strong>Twinkle mutations associated with autosomal dominant progressive external ophthalmoplegia lead to impaired helicase function and in vivo mtDNA replication stalling.</strong> Hum. Molec. Genet. 18: 328-340, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18971204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18971204</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18971204[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/ddn359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18971204">Goffart et al. (2009)</a> investigated the effects of dominant Twinkle PEO mutations in human cell culture and the Deletor mouse model, which expresses a dominant PEO mutation in Twinkle. Expression of dominant Twinkle mutations led to accumulation of mtDNA replication intermediates in cell culture. This indicated severe replication pausing or stalling and caused mtDNA depletion. Enhanced accumulation of replication intermediates was evident also in 6-week-old Deletor mice compared with wildtype littermates, even though mtDNA deletions accumulated in a late-onset fashion in this model. In vitro assays showed functional defects in the various Twinkle mutants and broadly agreed with the cell culture phenotypes such as the level of mtDNA depletion and the level of accumulation of replication intermediates. The authors suggested that mtDNA replication pausing or stalling is the common consequence of Twinkle PEO mutations that predisposes to multiple deletion formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18971204" 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="Tyynismaa, H., Carroll, C. J., Raimundo, N., Ahola-Erkkila, S., Wenz, T., Ruhanen, H., Guse, K., Hemminki, A., Peltola-Mjosund, K. E., Tulkki, V., Oresic, M., Moraes, C. T., Pietilainen, K., Hovatta, I., Suomalainen, A. <strong>Mitochondrial myopathy induces a starvation-like response.</strong> Hum. Molec. Genet. 19: 3948-3958, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20656789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20656789</a>] [<a href="https://doi.org/10.1093/hmg/ddq310" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20656789">Tyynismaa et al. (2010)</a> studied the skeletal muscle gene expression profiles of mice with late-onset mitochondrial myopathy due to a dominant mutation in twinkle. The global gene expression pattern of the mouse skeletal muscle showed induction of pathways involved in amino acid starvation response and activation of Akt (<a href="/entry/164730">164730</a>) signaling. Furthermore, the muscle showed induction of a fasting-related hormone, fibroblast growth factor-21 (FGF21; <a href="/entry/609436">609436</a>). Fgf21 was also elevated in the mouse serum, and the animals showed widespread changes in their lipid metabolism. The authors proposed that respiratory chain deficiency may induce a mitochondrial stress response, with local and global changes mimicking starvation, in a normal nutritional state, which may have important implications for understanding the metabolic consequences of mitochondrial myopathies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20656789" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=606075[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 3</strong>
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<p>In affected members of a Finnish family with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; <a href="/entry/609286">609286</a>), originally reported by <a href="#17" class="mim-tip-reference" title="Suomalainen, A., Majander, A., Haltia, M., Somer, H., Lonnqvist, J., Savontaus, M.-L., Peltonen, L. <strong>Multiple deletions of mitochondrial DNA in several tissues of a patient with severe retarded depression and familial progressive external ophthalmoplegia.</strong> J. Clin. Invest. 90: 61-66, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1634620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1634620</a>] [<a href="https://doi.org/10.1172/JCI115856" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1634620">Suomalainen et al. (1992)</a>, <a href="#16" class="mim-tip-reference" title="Spelbrink, J. N., Li, F.-Y., Tiranti, V., Nikali, K., Yuan, Q.-P., Tariq, M., Wanrooij, S., Garrido, N., Comi, G., Morandi, L., Santoro, L., Toscano, A., and 9 others. <strong>Human mitochondrial DNA deletions associated with mutations in the gene encoding twinkle, a phage T7 gene 4-like protein localized in mitochondria.</strong> Nature Genet. 28: 223-231, 2001. Note: Erratum: Nature Genet. 29: 100 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431692</a>] [<a href="https://doi.org/10.1038/90058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431692">Spelbrink et al. (2001)</a> identified a 39-bp duplication (nucleotides 1053-1092) of the C10ORF2 gene, resulting in a duplication of amino acids 352-364 of twinkle. There was complete segregation of this duplication with the disease phenotype in this pedigree. The mutation was not identified in over 400 Finnish controls. Individuals with this duplication had severe retarded depression and avoidant personality features in addition to PEO. Three autopsies from family members showed the highest amounts of deleted mtDNA in the cerebral cortex and basal ganglia (approximately 60% of total mtDNA), followed by skeletal muscle and heart, with only small amounts in kidney. This distribution, however, did not correspond exactly with the pattern of twinkle expression, arguing for variable sensitivity of different tissues to twinkle dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11431692+1634620" 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 DOMINANT 3</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">rs111033572 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033572;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=rs111033572" 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=rs111033572" 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 Pakistani family reported by <a href="#9" class="mim-tip-reference" title="Li, F. Y., Tariq, M., Croxen, R., Morten, K., Squier, W., Newsom-Davis, J., Beeson, D., Larsson, C. <strong>Mapping of autosomal dominant progressive external ophthalmoplegia to a 7-cM critical region on 10q24.</strong> Neurology 53: 1265-1271, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10522883/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10522883</a>] [<a href="https://doi.org/10.1212/wnl.53.6.1265" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10522883">Li et al. (1999)</a> with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; <a href="/entry/609286">609286</a>), <a href="#16" class="mim-tip-reference" title="Spelbrink, J. N., Li, F.-Y., Tiranti, V., Nikali, K., Yuan, Q.-P., Tariq, M., Wanrooij, S., Garrido, N., Comi, G., Morandi, L., Santoro, L., Toscano, A., and 9 others. <strong>Human mitochondrial DNA deletions associated with mutations in the gene encoding twinkle, a phage T7 gene 4-like protein localized in mitochondria.</strong> Nature Genet. 28: 223-231, 2001. Note: Erratum: Nature Genet. 29: 100 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431692</a>] [<a href="https://doi.org/10.1038/90058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431692">Spelbrink et al. (2001)</a> identified a heterozygous 1423G-C transversion in the C10ORF2 gene, resulting in an ala475-to-pro (A475P) substitution. This mutation was not identified in 194 controls of various ethnic origin, including 88 of Pakistani/Indian origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11431692+10522883" 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 DOMINANT 3</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">rs111033573 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033573;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=rs111033573" 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=rs111033573" 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=RCV000004881 OR RCV000508874 OR RCV002512779" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004881, RCV000508874, RCV002512779" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004881...</a>
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<p>In affected members of a large consanguineous Italian family segregating autosomal dominant progressive ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; <a href="/entry/609286">609286</a>), <a href="#16" class="mim-tip-reference" title="Spelbrink, J. N., Li, F.-Y., Tiranti, V., Nikali, K., Yuan, Q.-P., Tariq, M., Wanrooij, S., Garrido, N., Comi, G., Morandi, L., Santoro, L., Toscano, A., and 9 others. <strong>Human mitochondrial DNA deletions associated with mutations in the gene encoding twinkle, a phage T7 gene 4-like protein localized in mitochondria.</strong> Nature Genet. 28: 223-231, 2001. Note: Erratum: Nature Genet. 29: 100 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431692</a>] [<a href="https://doi.org/10.1038/90058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431692">Spelbrink et al. (2001)</a> identified an ala359-to-thr (A359T) substitution in the twinkle protein. Two homozygous individuals had a more severe phenotype with earlier onset than their heterozygous relatives. This mutation was not detected in a control group of 100 individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11431692" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Longley, M. J., Humble, M. M., Sharief, F. S., Copeland, W. C. <strong>Disease variants of the human mitochondrial DNA helicase encoded by C10orf2 differentially alter protein stability, nucleotide hydrolysis, and helicase activity.</strong> J. Biol. Chem. 285: 29690-29702, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20659899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20659899</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20659899[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/10.1074/jbc.M110.151795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20659899">Longley et al. (2010)</a> found that several disease-associated substitutions in p72, including A359T, which is located within the linker region, reduced the stability of the p72 hexamer. A359T also reduced p72 DNA-binding affinity and the velocities of p72 helicase and ATPase activities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20659899" 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 DOMINANT 3</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">rs111033574 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033574;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=rs111033574" 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=rs111033574" 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=RCV000004882 OR RCV002496262" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004882, RCV002496262" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004882...</a>
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<p>In affected members of a pedigree segregating autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; <a href="/entry/609286">609286</a>), <a href="#16" class="mim-tip-reference" title="Spelbrink, J. N., Li, F.-Y., Tiranti, V., Nikali, K., Yuan, Q.-P., Tariq, M., Wanrooij, S., Garrido, N., Comi, G., Morandi, L., Santoro, L., Toscano, A., and 9 others. <strong>Human mitochondrial DNA deletions associated with mutations in the gene encoding twinkle, a phage T7 gene 4-like protein localized in mitochondria.</strong> Nature Genet. 28: 223-231, 2001. Note: Erratum: Nature Genet. 29: 100 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431692</a>] [<a href="https://doi.org/10.1038/90058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431692">Spelbrink et al. (2001)</a> identified a trp474-to-cys (W474C) substitution in the twinkle protein. This mutation was not identified in 100 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11431692" 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 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 3</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">rs111033575 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033575;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=rs111033575" 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=rs111033575" 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=RCV000004883" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004883" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004883</a>
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<p>In affected members of a pedigree segregating autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; <a href="/entry/609286">609286</a>), <a href="#16" class="mim-tip-reference" title="Spelbrink, J. N., Li, F.-Y., Tiranti, V., Nikali, K., Yuan, Q.-P., Tariq, M., Wanrooij, S., Garrido, N., Comi, G., Morandi, L., Santoro, L., Toscano, A., and 9 others. <strong>Human mitochondrial DNA deletions associated with mutations in the gene encoding twinkle, a phage T7 gene 4-like protein localized in mitochondria.</strong> Nature Genet. 28: 223-231, 2001. Note: Erratum: Nature Genet. 29: 100 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431692</a>] [<a href="https://doi.org/10.1038/90058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431692">Spelbrink et al. (2001)</a> identified a trp315-to-leu (W315L) substitution in the twinkle protein. This mutation was in a moderately conserved segment of the linker region and was not identified in 100 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11431692" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0006" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0006 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 3</strong>
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TWNK, ARG354PRO
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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> rs111033576 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033576;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/rs111033576?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=rs111033576" 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=rs111033576" 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=RCV000004884" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004884" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004884</a>
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<p>In affected members of an Italian family segregating autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; <a href="/entry/609286">609286</a>), <a href="#16" class="mim-tip-reference" title="Spelbrink, J. N., Li, F.-Y., Tiranti, V., Nikali, K., Yuan, Q.-P., Tariq, M., Wanrooij, S., Garrido, N., Comi, G., Morandi, L., Santoro, L., Toscano, A., and 9 others. <strong>Human mitochondrial DNA deletions associated with mutations in the gene encoding twinkle, a phage T7 gene 4-like protein localized in mitochondria.</strong> Nature Genet. 28: 223-231, 2001. Note: Erratum: Nature Genet. 29: 100 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431692</a>] [<a href="https://doi.org/10.1038/90058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431692">Spelbrink et al. (2001)</a> identified a 1061G-C transversion in the C10ORF2 gene, resulting in an arg354-to-pro (R354P) substitution. This mutation was not identified in 100 normal controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11431692" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0007" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0007 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 3</strong>
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TWNK, LEU381PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs111033577 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033577;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=rs111033577" 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=rs111033577" 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=RCV000004885 OR RCV000508905" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004885, RCV000508905" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004885...</a>
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<p>In affected members of an Italian family segregating autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; <a href="/entry/609286">609286</a>), <a href="#16" class="mim-tip-reference" title="Spelbrink, J. N., Li, F.-Y., Tiranti, V., Nikali, K., Yuan, Q.-P., Tariq, M., Wanrooij, S., Garrido, N., Comi, G., Morandi, L., Santoro, L., Toscano, A., and 9 others. <strong>Human mitochondrial DNA deletions associated with mutations in the gene encoding twinkle, a phage T7 gene 4-like protein localized in mitochondria.</strong> Nature Genet. 28: 223-231, 2001. Note: Erratum: Nature Genet. 29: 100 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431692</a>] [<a href="https://doi.org/10.1038/90058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431692">Spelbrink et al. (2001)</a> identified a 1442T-C transition in the C10ORF2 gene, resulting in a leu381-to-pro (L381P) substitution. This mutation segregated strictly with the disease in this family and was not identified in 100 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11431692" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Longley, M. J., Humble, M. M., Sharief, F. S., Copeland, W. C. <strong>Disease variants of the human mitochondrial DNA helicase encoded by C10orf2 differentially alter protein stability, nucleotide hydrolysis, and helicase activity.</strong> J. Biol. Chem. 285: 29690-29702, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20659899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20659899</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20659899[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/10.1074/jbc.M110.151795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20659899">Longley et al. (2010)</a> found that several disease-associated substitutions in p72, including L381P, which is located between the linker region and helicase domain, reduced the stability of the p72 hexamer. L381P also increased the rate of ATP hydrolysis by p72 over that measured for wildtype p72. However, elevated ATP hydrolysis was not accompanied by proportionately higher DNA helicase activity, implying that nucleotide hydrolysis and DNA translocation may be partially uncoupled by the L381P substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20659899" 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="0008" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0008 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, DIGENIC</strong>
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TWNK, ARG334GLN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28937887 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28937887;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=rs28937887" 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=rs28937887" 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=RCV000004886 OR RCV000508769 OR RCV001093424 OR RCV001542762 OR RCV002288465" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004886, RCV000508769, RCV001093424, RCV001542762, RCV002288465" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004886...</a>
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<p>In a sporadic case of progressive external ophthalmoplegia (see <a href="/entry/609286">609286</a> and <a href="/entry/157640">157640</a>), <a href="#21" 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 heterozygosity for a 1031G-A transition in the C10ORF2 gene, resulting in an arg334-to-gln (R334Q) mutation, and heterozygosity for a gly884-to-ser mutation in the POLG gene (G884S; <a href="/entry/174763#0006">174763.0006</a>), indicating a digenic mode of inheritance. Clinical onset in the patient was at 52 years of age with blepharoptosis, depression, and levodopa-responsive Parkinson disease. Later she suffered from severe dysphagia leading to cachexia and necessitating enteric feeding. Sudden death, attributed to cardiac arrest, occurred at age 66 years. <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>
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<a id="0009" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0009 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 3</strong>
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TWNK, SER369TYR
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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> rs111033579 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033579;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/rs111033579?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=rs111033579" 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=rs111033579" 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=RCV000004887" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004887" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004887</a>
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<p>In affected members of a large family with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; <a href="/entry/609286">609286</a>), <a href="#8" class="mim-tip-reference" title="Lewis, S., Hutchison, W., Thyagarajan, D., Dahl, H.-H. M. <strong>Clinical and molecular features of adPEO due to mutations in the twinkle gene.</strong> J. Neurol. Sci. 201: 39-44, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12163192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12163192</a>] [<a href="https://doi.org/10.1016/s0022-510x(02)00190-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12163192">Lewis et al. (2002)</a> identified a heterozygous 1106C-A transversion in the C10ORF2 gene, resulting in a ser369-to-tyr (S369Y) substitution in the linker region of the protein. Affected members of a second presumably unrelated family were found to have the same mutation. Both families originated from the same region in Tasmania, and haplotype analysis showed a common haplotype. The S369Y mutation was not identified in 100 control individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12163192" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 3</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">rs80356543 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356543;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=rs80356543" 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=rs80356543" 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=RCV000004888 OR RCV000020867" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004888, RCV000020867" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004888...</a>
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<p>In 2 sibs with autosomal dominant progressive external ophthalmoplegia with mitochondrial deletions-3 (PEOA3; <a href="/entry/609286">609286</a>), <a href="#7" class="mim-tip-reference" title="Hudson, G., Deschauer, M., Busse, K., Zierz, S., Chinnery, P. F. <strong>Sensory ataxic neuropathy due to a novel C10ORF2 mutation with probable germline mosaicism.</strong> Neurology 64: 371-373, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15668446/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15668446</a>] [<a href="https://doi.org/10.1212/01.WNL.0000149767.51152.83" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15668446">Hudson et al. (2005)</a> identified a heterozygous 955A-G transition in the C10ORF2 gene, resulting in a lys319-to-glu (K319E) substitution. The 45-year-old proband had ptosis, external ophthalmoplegia, moderate proximal weakness of the legs, severe sensory ataxia, and moderate dementia. His sister had ptosis, ophthalmoplegia, proximal leg weakness, dysarthria, ataxia, and signs of a sensory neuropathy. She subsequently developed dementia, diabetes, and seizures. At age 41 she developed status epilepticus and died. The mutation was not identified in the parents' blood, hair follicles, buccal mucosa, or urinary epithelium, indicating germline mosaicism. <a href="#7" class="mim-tip-reference" title="Hudson, G., Deschauer, M., Busse, K., Zierz, S., Chinnery, P. F. <strong>Sensory ataxic neuropathy due to a novel C10ORF2 mutation with probable germline mosaicism.</strong> Neurology 64: 371-373, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15668446/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15668446</a>] [<a href="https://doi.org/10.1212/01.WNL.0000149767.51152.83" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15668446">Hudson et al. (2005)</a> emphasized that the findings broadened the phenotype associated with C10ORF2 mutations, and noted the phenotypic overlap with sensory ataxia neuropathy, dysarthria, and ophthalmoparesis (SANDO; <a href="/entry/607459">607459</a>), The authors also noted that the mutation caused the replacement of a basic amino acid with an acidic amino acid in a conserved region of the protein, which may have accounted for the more severe phenotype observed in their patients compared to other patients with C10ORF2 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15668446" 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 7 (HEPATOCEREBRAL 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> rs80356544 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356544;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/rs80356544?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=rs80356544" 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=rs80356544" 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=RCV000004889" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004889" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004889</a>
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<p>In 2 Algerian sibs and a first cousin with autosomal recessive mitochondrial DNA depletion syndrome-7 (MTDPS7; <a href="/entry/271245">271245</a>), <a href="#14" class="mim-tip-reference" title="Sarzi, E., Goffart, S., Serre, V., Chretien, D., Slama, A., Munnich, A., Spelbrink, J. N., Rotig, A. <strong>Twinkle helicase (PEO1) gene mutation causes mitochondrial DNA depletion.</strong> Ann. Neurol. 62: 579-587, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17722119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17722119</a>] [<a href="https://doi.org/10.1002/ana.21207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17722119">Sarzi et al. (2007)</a> identified a homozygous 1370C-T transition in the C10ORF2 gene, resulting in a thr457-to-ile (T457I) substitution. All 3 patients were born of first-cousin parents and showed a severe hepatocerebral phenotype characterized by neonatal hypotonia, mild liver insufficiency, increased serum and CSF lactate, psychomotor retardation, seizures, and peripheral neuropathy. All 3 patients died by age 3 years. Mitochondrial DNA depletion was severe in 2 patients examined, with mtDNA levels in liver of 8% and 5% of normal, respectively. Molecular modeling predicted that the mutation is located in the interface between 2 monomers of the hexameric enzyme. In vitro functional expression studies showed that the T457I mutant protein had a more than 50% reduction in helicase activity. Family members who were presumed obligate carriers were unaffected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17722119" 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 7 (HEPATOCEREBRAL 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> rs80356540 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356540;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/rs80356540?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=rs80356540" 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=rs80356540" 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=RCV000020865 OR RCV000199894" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000020865, RCV000199894" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000020865...</a>
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<p>In Finnish patients with mitochondrial DNA depletion syndrome-7 (MTDPS7; <a href="/entry/271245">271245</a>) manifest as infantile-onset autosomal recessive spinocerebellar ataxia, <a href="#12" class="mim-tip-reference" title="Nikali, K., Suomalainen, A., Saharinen, J., Kuokkanen, M., Spelbrink, J. N., Lonnqvist, T., Peltonen, L. <strong>Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins twinkle and twinky.</strong> Hum. Molec. Genet. 14: 2981-2990, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16135556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16135556</a>] [<a href="https://doi.org/10.1093/hmg/ddi328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16135556">Nikali et al. (2005)</a> identified homozygosity for a founder mutation in exon 3 of the C10ORF2 gene: a 1708A-G transition resulting in a tyr508-to-cys (Y508C) substitution in the twinkle and twinky proteins. One other Finnish patient was compound heterozygous for Y508C inherited from his mother and a silent mutation (1472C-T) in exon 2 of C10ORF2 inherited from his father that affected allelic expression levels. Carrier frequency for the mutation peaked at approximately 2.5% in south central Finland. The Y508C mutation was not found in unaffected family members, 712 Finnish control samples, or 95 non-Finnish controls; the silent mutation was not found in 207 Finnish or 95 foreign controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16135556" 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 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 3</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> rs137852956 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852956;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/rs137852956?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=rs137852956" 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=rs137852956" 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=RCV000004891 OR RCV001289123" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004891, RCV001289123" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004891...</a>
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<p>In a 71-year-old woman who developed autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; <a href="/entry/609286">609286</a>) at age 51, <a href="#22" class="mim-tip-reference" title="Van Hove, J. L. K., Cunningham, V., Rice, C., Ringel, S. P., Zhang, Q., Chou, P.-C., Truong, C. K., Wong, L.-J. C. <strong>Finding twinkle in the eyes of a 71-year-old lady: A case report and review of the genotypic and phenotypic spectrum of TWINKLE-related dominant disease.</strong> Am. J. Med. Genet. 149A: 861-867, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19353676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19353676</a>] [<a href="https://doi.org/10.1002/ajmg.a.32731" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19353676">Van Hove et al. (2009)</a> identified a heterozygous 908G-A transition in exon 1 of the TWNK gene, resulting in an arg303-to-gln (R303Q) substitution in the first amino acid of primase motif V. The mutation was not found in 250 control chromosomes. Other clinical features included cataracts, adult-onset diabetes mellitus, distal paresthesias, sensorineural hearing loss, mild sensory ataxia, and chronic progressive limb-girdle muscle weakness. Brain MRI showed scattered white matter changes in the subcortical and periventricular regions. Skeletal muscle biopsy showed a few ragged-red fibers and multiple mtDNA deletions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19353676" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0014 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 3</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> rs267606682 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606682;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/rs267606682?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=rs267606682" 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=rs267606682" 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=RCV000004892 OR RCV000523637" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004892, RCV000523637" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004892...</a>
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<p>In 5 patients from 2 unrelated French families with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; <a href="/entry/609286">609286</a>), <a href="#2" class="mim-tip-reference" title="Echaniz-Laguna, A., Chanson, J. B., Wilhelm, J. M., Sellal, F., Mayencon, M., Mohr, M., Tranchant, C., de Camaret, B. M. <strong>A novel variation in the Twinkle linker region causing late-onset dementia.</strong> Neurogenetics 11: 21-25, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19513767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19513767</a>] [<a href="https://doi.org/10.1007/s10048-009-0202-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19513767">Echaniz-Laguna et al. (2010)</a> identified a heterozygous 1120C-T transition in the C10ORF2 gene, resulting in an arg374-to-trp (R374W) substitution in the linker region. Common features included ptosis, ophthalmoplegia, hearing loss, sensory axonal neuropathy, and proximal muscle weakness. The older patients, including deceased affected family members, developed abnormal gait, dysphagia, dysphonia, and late-onset dementia in their seventies and eighties. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19513767" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0015 MITOCHONDRIAL DNA DEPLETION SYNDROME 7 (HEPATOCEREBRAL TYPE)</strong>
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TWNK, ALA318THR
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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> rs80356542 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356542;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/rs80356542?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=rs80356542" 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=rs80356542" 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=RCV000020866 OR RCV002251876" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000020866, RCV002251876" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000020866...</a>
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<p>In 2 Finnish sibs with mtDNA depletion syndrome-7 (MTDPS7; <a href="/entry/271245">271245</a>), manifest as infantile-onset spinocerebellar ataxia, <a href="#6" class="mim-tip-reference" title="Hakonen, A. H., Isohanni, P., Paetau, A., Herva, R., Suomalainen, A., Lonnqvist, T. <strong>Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion.</strong> Brain 130: 3032-3040, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17921179/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17921179</a>] [<a href="https://doi.org/10.1093/brain/awm242" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17921179">Hakonen et al. (2007)</a> identified compound heterozygosity for 2 mutations in the C10ORF2 gene: a 952G-A transition, resulting in an ala318-to-thr (A318T) substitution, and the Y508C mutation (<a href="#0012">606075.0012</a>). The phenotype was severe, showing hypotonia, athetosis, sensory neuropathy, ataxia, hearing deficit, ophthalmoplegia, and refractory epilepsy. The older sib died at age 4.5 years of status epilepticus. One patient had mtDNA depletion in the liver. Each unaffected parent was heterozygous for 1 of the mutations. The A318T mutation was not present in 120 Finnish control chromosomes. <a href="#6" class="mim-tip-reference" title="Hakonen, A. H., Isohanni, P., Paetau, A., Herva, R., Suomalainen, A., Lonnqvist, T. <strong>Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion.</strong> Brain 130: 3032-3040, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17921179/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17921179</a>] [<a href="https://doi.org/10.1093/brain/awm242" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17921179">Hakonen et al. (2007)</a> noted that the phenotype was reminiscent of Alpers syndrome (MTDPS4B; <a href="/entry/203700">203700</a>), which is caused by mutation in the POLG gene (<a href="/entry/174763">174763</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17921179" 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="0016" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0016 PERRAULT SYNDROME 5</strong>
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TWNK, ARG391HIS
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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> rs556445621 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs556445621;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/rs556445621?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=rs556445621" 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=rs556445621" 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=RCV000149470 OR RCV000290037 OR RCV000305281 OR RCV000345001 OR RCV000403533 OR RCV002516005 OR RCV002516006" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000149470, RCV000290037, RCV000305281, RCV000345001, RCV000403533, RCV002516005, RCV002516006" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000149470...</a>
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<span class="mim-text-font">
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<p>In 2 Japanese sisters with Perrault syndrome-5 (PRLTS5; <a href="/entry/616138">616138</a>), <a href="#11" class="mim-tip-reference" title="Morino, H., Pierce, S. B., Matsuda, Y., Walsh, T., Ohsawa, R., Newby, M., Hiraki-Kamon, K., Kuramochi, M., Lee, M. K., Klevit, R. E., Martin, A., Maruyama, H., King, M.-C., Kawakami, H. <strong>Mutations in Twinkle primase-helicase cause Perrault syndrome with neurologic features.</strong> Neurology 83: 2054-2061, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25355836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25355836</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25355836[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/10.1212/WNL.0000000000001036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25355836">Morino et al. (2014)</a> identified compound heterozygous mutations in the C10ORF2 gene: a c.1172G-A transition resulting in an arg391-to-his (R391H) substitution at a less conserved residue, and a c.1754A-G transition resulting in an asn585-to-ser (N585S; <a href="#0017">606075.0017</a>) substitution at a conserved residue. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variants were filtered against the dbSNP (build 137), 1000 Genomes Project, and Exome Sequencing Project databases and were absent from in-house control exomes. Both mutations occurred in the helicase domain and were predicted to adversely affect enzyme activity based on structure, but functional studies of the variants were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25355836" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0017" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0017 PERRAULT SYNDROME 5</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> rs672601360 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs672601360;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/rs672601360?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=rs672601360" 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=rs672601360" 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=RCV000149471 OR RCV002514865 OR RCV003556196" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000149471, RCV002514865, RCV003556196" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000149471...</a>
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<span class="mim-text-font">
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<p>For discussion of the asn585-to-ser (N585S) mutation in the C10ORF2 gene that was found in 2 sisters with Perrault syndrome-5 (PRLTS5; <a href="/entry/616138">616138</a>) by <a href="#11" class="mim-tip-reference" title="Morino, H., Pierce, S. B., Matsuda, Y., Walsh, T., Ohsawa, R., Newby, M., Hiraki-Kamon, K., Kuramochi, M., Lee, M. K., Klevit, R. E., Martin, A., Maruyama, H., King, M.-C., Kawakami, H. <strong>Mutations in Twinkle primase-helicase cause Perrault syndrome with neurologic features.</strong> Neurology 83: 2054-2061, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25355836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25355836</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25355836[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/10.1212/WNL.0000000000001036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25355836">Morino et al. (2014)</a>, see <a href="#0016">606075.0016</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25355836" 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 PERRAULT SYNDROME 5</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> rs672601361 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs672601361;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/rs672601361?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=rs672601361" 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=rs672601361" 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=RCV000149472 OR RCV002516007 OR RCV003556197" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000149472, RCV002516007, RCV003556197" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000149472...</a>
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<span class="mim-text-font">
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<p>In 2 sisters of paternal Greek ancestry and maternal mixed European ancestry with Perrault syndrome-5 (PRLTS5; <a href="/entry/616138">616138</a>), <a href="#11" class="mim-tip-reference" title="Morino, H., Pierce, S. B., Matsuda, Y., Walsh, T., Ohsawa, R., Newby, M., Hiraki-Kamon, K., Kuramochi, M., Lee, M. K., Klevit, R. E., Martin, A., Maruyama, H., King, M.-C., Kawakami, H. <strong>Mutations in Twinkle primase-helicase cause Perrault syndrome with neurologic features.</strong> Neurology 83: 2054-2061, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25355836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25355836</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25355836[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/10.1212/WNL.0000000000001036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25355836">Morino et al. (2014)</a> identified compound heterozygous mutations in the C10ORF2 gene: a c.1321T-G transversion resulting in a trp441-to-gly (W441G) substitution at a conserved residue, and a c.1519G-A transition resulting in a val507-to-ile (V507I; <a href="#0019">606075.0019</a>) substitution at a less well-conserved residue. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variants were filtered against the dbSNP (build 137), 1000 Genomes Project, and Exome Sequencing Project databases and were absent from in-house control exomes: V507I was found once in the Exome Sequencing Project database. Both mutations occurred in the helicase domain and were predicted to adversely affect enzyme activity based on structure, but functional studies of the variants were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25355836" 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> rs369588002 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs369588002;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/rs369588002?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=rs369588002" 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=rs369588002" 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=RCV000149473 OR RCV000521090 OR RCV002514866 OR RCV003479021" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000149473, RCV000521090, RCV002514866, RCV003479021" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000149473...</a>
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<p>For discussion of the val507-to-ile (V507I) mutation in the C10ORF2 gene that was found in 2 sisters with Perrault syndrome-5 (PRLTS5; <a href="/entry/616138">616138</a>) by <a href="#11" class="mim-tip-reference" title="Morino, H., Pierce, S. B., Matsuda, Y., Walsh, T., Ohsawa, R., Newby, M., Hiraki-Kamon, K., Kuramochi, M., Lee, M. K., Klevit, R. E., Martin, A., Maruyama, H., King, M.-C., Kawakami, H. <strong>Mutations in Twinkle primase-helicase cause Perrault syndrome with neurologic features.</strong> Neurology 83: 2054-2061, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25355836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25355836</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25355836[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/10.1212/WNL.0000000000001036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25355836">Morino et al. (2014)</a>, see <a href="#0018">606075.0018</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25355836" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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[<a href="https://doi.org/10.1002/ana.10430" target="_blank">Full Text</a>]
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<strong>A novel variation in the Twinkle linker region causing late-onset dementia.</strong>
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[<a href="https://doi.org/10.1007/s10048-009-0202-4" target="_blank">Full Text</a>]
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Farge, G., Holmlund, T., Khvorostova, J., Rofougaran, R., Hofer, A., Falkenberg, M.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18039713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18039713</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18039713" 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/nar/gkm1025" target="_blank">Full Text</a>]
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Goffart, S., Cooper, H. M., Tyynismaa, H., Wanrooij, S., Suomalainen, A., Spelbrink, J. N.
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<strong>Twinkle mutations associated with autosomal dominant progressive external ophthalmoplegia lead to impaired helicase function and in vivo mtDNA replication stalling.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18971204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18971204</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18971204[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=18971204" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Hakonen, A. H., Goffart, S., Marjavaara, S., Paetau, A., Cooper, H., Mattila, K., Lampinen, M., Sajantila, A., Lonnqvist, T., Spelbrink, J. N., Suomalainen, A.
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Hum. Molec. Genet. 17: 3822-3835, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18775955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18775955</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18775955" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Hakonen, A. H., Isohanni, P., Paetau, A., Herva, R., Suomalainen, A., Lonnqvist, T.
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<strong>Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion.</strong>
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[<a href="https://doi.org/10.1093/brain/awm242" target="_blank">Full Text</a>]
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Hudson, G., Deschauer, M., Busse, K., Zierz, S., Chinnery, P. F.
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<strong>Sensory ataxic neuropathy due to a novel C10ORF2 mutation with probable germline mosaicism.</strong>
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Morino, H., Pierce, S. B., Matsuda, Y., Walsh, T., Ohsawa, R., Newby, M., Hiraki-Kamon, K., Kuramochi, M., Lee, M. K., Klevit, R. E., Martin, A., Maruyama, H., King, M.-C., Kawakami, H.
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<strong>Mutations in Twinkle primase-helicase cause Perrault syndrome with neurologic features.</strong>
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Neurology 83: 2054-2061, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25355836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25355836</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25355836[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=25355836" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/WNL.0000000000001036" target="_blank">Full Text</a>]
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<a id="12" class="mim-anchor"></a>
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<a id="Nikali2005" class="mim-anchor"></a>
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<div class="">
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Nikali, K., Suomalainen, A., Saharinen, J., Kuokkanen, M., Spelbrink, J. N., Lonnqvist, T., Peltonen, L.
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<strong>Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins twinkle and twinky.</strong>
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Hum. Molec. Genet. 14: 2981-2990, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16135556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16135556</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16135556" 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/ddi328" target="_blank">Full Text</a>]
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<a id="Peter2019" class="mim-anchor"></a>
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Peter, B., Farge, G., Pardo-Hernandez, C., Tangefjord, S., Falkenberg, M.
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<strong>Structural basis for adPEO-causing mutations in the mitochondrial TWINKLE helicase.</strong>
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Hum. Molec. Genet. 28: 1090-1099, 2019. Note: Erratum: Hum. Molec. Genet. 29: 528 only, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30496414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30496414</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30496414" 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/ddy415" target="_blank">Full Text</a>]
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<a id="Sarzi2007" class="mim-anchor"></a>
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<div class="">
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Sarzi, E., Goffart, S., Serre, V., Chretien, D., Slama, A., Munnich, A., Spelbrink, J. N., Rotig, A.
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<strong>Twinkle helicase (PEO1) gene mutation causes mitochondrial DNA depletion.</strong>
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Ann. Neurol. 62: 579-587, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17722119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17722119</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17722119" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.21207" target="_blank">Full Text</a>]
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<a id="Sen2012" class="mim-anchor"></a>
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Sen, D., Nandakumar, D., Tang, G.-Q., Patel, S. S.
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<strong>Human mitochondrial DNA helicase TWINKLE is both an unwinding and annealing helicase.</strong>
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J. Biol. Chem. 287: 14545-14556, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22383523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22383523</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22383523[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=22383523" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M111.309468" target="_blank">Full Text</a>]
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<a id="Spelbrink2001" class="mim-anchor"></a>
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Spelbrink, J. N., Li, F.-Y., Tiranti, V., Nikali, K., Yuan, Q.-P., Tariq, M., Wanrooij, S., Garrido, N., Comi, G., Morandi, L., Santoro, L., Toscano, A., and 9 others.
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<strong>Human mitochondrial DNA deletions associated with mutations in the gene encoding twinkle, a phage T7 gene 4-like protein localized in mitochondria.</strong>
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Nature Genet. 28: 223-231, 2001. Note: Erratum: Nature Genet. 29: 100 only, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431692</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11431692" 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/10.1038/90058" target="_blank">Full Text</a>]
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<a id="Suomalainen1992" class="mim-anchor"></a>
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Suomalainen, A., Majander, A., Haltia, M., Somer, H., Lonnqvist, J., Savontaus, M.-L., Peltonen, L.
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<strong>Multiple deletions of mitochondrial DNA in several tissues of a patient with severe retarded depression and familial progressive external ophthalmoplegia.</strong>
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J. Clin. Invest. 90: 61-66, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1634620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1634620</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1634620" 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/10.1172/JCI115856" target="_blank">Full Text</a>]
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<a id="Tyynismaa2010" class="mim-anchor"></a>
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Tyynismaa, H., Carroll, C. J., Raimundo, N., Ahola-Erkkila, S., Wenz, T., Ruhanen, H., Guse, K., Hemminki, A., Peltola-Mjosund, K. E., Tulkki, V., Oresic, M., Moraes, C. T., Pietilainen, K., Hovatta, I., Suomalainen, A.
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<strong>Mitochondrial myopathy induces a starvation-like response.</strong>
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Hum. Molec. Genet. 19: 3948-3958, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20656789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20656789</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20656789" 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/ddq310" target="_blank">Full Text</a>]
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<a id="Tyynismaa2005" class="mim-anchor"></a>
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Tyynismaa, H., Mjosund, K. P., Wanrooij, S., Lappalainen, I., Ylikallio, E., Jalanko, A., Spelbrink, J. N., Paetau, A., Suomalainen, A.
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<strong>Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice.</strong>
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Proc. Nat. Acad. Sci. 102: 17687-17692, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16301523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16301523</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16301523[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=16301523" 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/10.1073/pnas.0505551102" target="_blank">Full Text</a>]
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<a id="Tyynismaa2004" class="mim-anchor"></a>
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Tyynismaa, H., Sembongi, H., Bokori-Brown, M., Granycome, C., Ashley, N., Poulton, J., Jalanko, A., Spelbrink, J. N., Holt, I. J., Suomalainen, A.
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<strong>Twinkle helicase is essential for mtDNA maintenance and regulates mtDNA copy number.</strong>
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Hum. Molec. Genet. 13: 3219-3227, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15509589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15509589</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15509589" 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/ddh342" target="_blank">Full Text</a>]
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<a id="Van Goethem2003" class="mim-anchor"></a>
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Van Goethem, G., Lofgren, A., Dermaut, B., Ceuterick, C., Martin, J.-J., Van Broeckhoven, C.
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<strong>Digenic progressive external ophthalmoplegia in a sporadic patient: recessive mutations in POLG and C10orf2/Twinkle. (Letter)</strong>
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Hum. Mutat. 22: 175-176, 2003.
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[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://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'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.10246" target="_blank">Full Text</a>]
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Van Hove, J. L. K., Cunningham, V., Rice, C., Ringel, S. P., Zhang, Q., Chou, P.-C., Truong, C. K., Wong, L.-J. C.
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<strong>Finding twinkle in the eyes of a 71-year-old lady: A case report and review of the genotypic and phenotypic spectrum of TWINKLE-related dominant disease.</strong>
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Am. J. Med. Genet. 149A: 861-867, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19353676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19353676</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19353676" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.32731" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </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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Bao Lige - updated : 10/03/2019
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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George E. Tiller - updated : 06/20/2017<br>Cassandra L. Kniffin - updated : 12/16/2014<br>Patricia A. Hartz - updated : 2/27/2013<br>Patricia A. Hartz - updated : 1/9/2012<br>Cassandra L. Kniffin - updated : 12/9/2010<br>Cassandra L. Kniffin - updated : 3/18/2010<br>Cassandra L. Kniffin - updated : 3/1/2010<br>Cassandra L. Kniffin - updated : 10/16/2009<br>George E. Tiller - updated : 4/20/2009<br>George E. Tiller - updated : 4/10/2008<br>Cassandra L. Kniffin - updated : 3/31/2008<br>George E. Tiller - updated : 5/21/2007<br>Patricia A. Hartz - updated : 1/27/2006<br>Cassandra L. Kniffin - updated : 5/24/2005<br>Cassandra L. Kniffin - updated : 4/29/2005<br>Cassandra L. Kniffin - updated : 3/30/2005<br>Cassandra L. Kniffin - updated : 3/30/2005<br>Victor A. McKusick - updated : 9/9/2003<br>Cassandra L. Kniffin - updated : 5/6/2003
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Creation Date:
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Ada Hamosh : 6/28/2001
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carol : 09/14/2020
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mgross : 10/03/2019<br>mgross : 10/03/2019<br>alopez : 06/20/2017<br>carol : 03/27/2017<br>mcolton : 07/29/2015<br>carol : 7/10/2015<br>mcolton : 7/7/2015<br>alopez : 12/16/2014<br>mcolton : 12/16/2014<br>ckniffin : 12/16/2014<br>mgross : 3/7/2013<br>terry : 2/27/2013<br>terry : 11/28/2012<br>mgross : 1/9/2012<br>mgross : 1/9/2012<br>terry : 1/9/2012<br>terry : 2/14/2011<br>terry : 2/14/2011<br>carol : 12/21/2010<br>ckniffin : 12/9/2010<br>ckniffin : 12/6/2010<br>wwang : 3/22/2010<br>ckniffin : 3/18/2010<br>wwang : 3/3/2010<br>ckniffin : 3/1/2010<br>wwang : 11/6/2009<br>ckniffin : 10/16/2009<br>alopez : 4/20/2009<br>terry : 2/2/2009<br>carol : 4/10/2008<br>wwang : 4/4/2008<br>ckniffin : 3/31/2008<br>wwang : 6/5/2007<br>terry : 5/21/2007<br>mgross : 2/2/2006<br>terry : 1/27/2006<br>wwang : 6/15/2005<br>wwang : 6/13/2005<br>ckniffin : 5/24/2005<br>ckniffin : 4/29/2005<br>carol : 4/28/2005<br>ckniffin : 4/4/2005<br>carol : 3/30/2005<br>carol : 3/30/2005<br>ckniffin : 3/30/2005<br>ckniffin : 3/29/2005<br>ckniffin : 2/21/2005<br>tkritzer : 9/15/2003<br>tkritzer : 9/9/2003<br>tkritzer : 5/15/2003<br>ckniffin : 5/6/2003<br>carol : 6/29/2001<br>mgross : 6/29/2001<br>mgross : 6/28/2001<br>mgross : 6/28/2001<br>carol : 6/28/2001<br>carol : 6/28/2001
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<h3>
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<span class="mim-font">
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<strong>*</strong> 606075
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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TWINKLE mtDNA HELICASE; TWNK
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</h3>
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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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</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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CHROMOSOME 10 OPEN READING FRAME 2; C10ORF2<br />
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T7 GENE 4-LIKE PROTEIN WITH INTRAMITOCHONDRIAL NUCLEOID LOCALIZATION; TWINKLE<br />
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p72
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</span>
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</h4>
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<p>
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<span class="mim-font">
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Other entities represented in this entry:
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</p>
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<span class="h3 mim-font">
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TWINKY, INCLUDED
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: TWNK</em></strong>
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</p>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 724227000;
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 10q24.31
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Genomic coordinates <span class="small">(GRCh38)</span> : 10:100,987,543-100,994,403 </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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<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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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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Location
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<th>
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Phenotype
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</th>
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Phenotype <br /> MIM number
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<th>
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Inheritance
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<th>
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Phenotype <br /> mapping key
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<tbody>
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<td rowspan="3">
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<span class="mim-font">
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10q24.31
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<td>
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<span class="mim-font">
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Mitochondrial DNA depletion syndrome 7 (hepatocerebral type)
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<td>
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<span class="mim-font">
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271245
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<td>
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<span class="mim-font">
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Autosomal recessive
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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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<span class="mim-font">
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Perrault syndrome 5
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</td>
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<td>
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<span class="mim-font">
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616138
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</span>
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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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<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 with mitochondrial DNA deletions, autosomal dominant 3
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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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609286
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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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</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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<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>Description</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 TWNK gene encodes a mitochondrial protein with structural similarity to the phage T7 primase/helicase (GP4) and other hexameric ring helicases. The twinkle protein colocalizes with mtDNA in mitochondrial nucleoids, and its name derives from the unusual localization pattern reminiscent of twinkling stars (summary by Spelbrink et al., 2001). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Spelbrink et al. (2001) identified the C10ORF2 gene, which encodes a protein similar to T7 GP4, by searching for open reading frames (ORFs) in a region linked to PEOA3 (609286) on 10q24. C10ORF2 has a mitochondrial targeting sequence at the N terminus. The predicted full-length protein, which the authors designated twinkle, has 684 amino acids with a molecular mass of 77 kD. Spelbrink et al. (2001) identified a splice variant resulting from the use of a downstream exon 4 splice donor site that leads to a 43-bp insertion between the regular exon 4-exon 5 sequence. The protein encoded by the variant mRNA, which the authors called twinky, has a molecular mass of 66 kD and has 582 amino acids; it lacks residues 579 through 684 and terminates with 4 unique amino acids. Both cDNA variants, when expressed transiently in HEK293T cells, directed the synthesis of proteins close to the expected molecular masses. The authors found that C. elegans and Drosophila have similar proteins, also related to T7 GP4. S. pombe has a few homologs with low similarity, but Spelbrink et al. (2001) could not identify a related sequence in S. cerevisiae. Multiple sequence alignment of the various proteins showed greatest similarity in the domain responsible for helicase activity in the phage T7 protein, which is located in its C terminus. The degree of identity between the human and a partial mouse sequence is approximately 85%, whereas the identity between the mammalian and vertebrate sequences is 35 to 40%. Northern blot analysis detected full-length mRNAs of 4 kb, significantly larger than the 2.1-kb ORF. Twinkle was expressed at high relative levels in skeletal muscle and pancreas and at low levels in heart. The relative level of twinkle expression in skeletal muscle was probably underestimated because of the strong crossreacting alpha-actin mRNA species just below the beta-actin mRNA. Twinkle is localized to mitochondrial nucleoids and shows an unusual localization pattern reminiscent of twinkling stars. Cells overexpressing twinkle had a modestly increased mtDNA helicase activity. The function of twinkle was presumed to be critical for lifetime maintenance of human mitochondrial integrity. </p><p>Van Hove et al. (2009) noted that the twinkle protein contains 3 functional domains: a 3-prime helicase region, required for mtDNA replication, a linker region involved in oligomerization into a hexamer required for helicase activity, and a 5-primase domain. Most pathogenic mutations occur in the helicase or linker regions. </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>Farge et al. (2008) showed that purified recombinant human TWINKLE formed hexamers, even in the absence of Mg(2+) or ATP, at high ionic strength. The C-terminal domain of TWINKLE was essential for hexamer formation, but the N-terminal domain also contributed to proper hexamerization. TWINKLE interacted with both single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA), preferably with long ssDNA or dsDNA. The C-terminal helicase domain of TWINKLE was responsible for DNA binding, but the N-terminal domain specifically contributed to ssDNA-binding activity. ssDNA stimulated the intrinsic ATPase activity of TWINKLE. The N-terminal region of TWINKLE was not absolutely required for its ATPase activity, but it had a positive effect on levels of ATPase activity, as well as ssDNA-dependent stimulation, helicase activity, and DNA synthesis on a duplex DNA template. </p><p>Using recombinant protein expressed in E. coli, Longley et al. (2010) showed that human C10ORF2, which they called p72, bound both ssDNA and dsDNA, catalyzed DNA unwinding, and required ATP and Mg(2+) for helicase activity. </p><p>Sen et al. (2012) showed that recombinant human twinkle formed oligomers spontaneously, but that it formed hexamers specifically in the presence of MgUTP, which appeared to stabilize the hexameric state. Twinkle bound both ssDNA and dsDNA via different binding sites with distinct binding affinities. DNA binding was independent of Mg(2+) or nucleotide triphosphates (NTP). Twinkle showed unwinding activity predominantly with 5-prime-tailed dsDNA substrates in the presence of several NTPs and Mg(2+), and it required its NTPase activity for dsDNA unwinding. Unwinding of dsDNA was facilitated by inclusion of T7 gp2.5 single strand-binding protein or complementary ssDNA to prevent reannealing of the unwound displaced strand. Twinkle also showed UTP-independent DNA annealing of 2 ssDNA strands in the absence of gp2.5 or complementary ssDNA. Sen et al. (2012) concluded that twinkle is a bifunctional helicase with both unwinding and annealing activities. </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>Biochemical Features</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>TWINKLE comprises a DNA helicase domain and a primase domain joined by a flexible linker helix. Using negative stain analysis, Peter et al. (2019) showed that TWINKLE was present as a mixture of hexameric and heptameric species. These oligomers formed star-like structures with the helicase domain forming an internal ring and the primase domain extending into the solvent. TWINKLE underwent conformational changes in the presence of nucleotides, leading to structural compaction and repositioning of the primase domain and the formation of hexamers and heptamers with smaller diameters. The linker helix contacted the neighboring helicase domain, connecting 1 monomer to the next. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions, Autosomal Dominant, 3</em></strong></p><p>
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In a Finnish family and a Pakistani family with autosomal dominant progressive external ophthalmoplegia (PEOA3; 609286), Spelbrink et al. (2001) identified 2 different heterozygous mutations in the C10ORF2 gene (606075.0001 and 606075.0002, respectively). Nine additional heterozygous mutations in the C10ORF2 gene (see, e.g., 606075.0003-606075.0007) were identified in 9 unrelated Italian PEO families and 1 British PEO family out of over 70 PEO families tested. </p><p>One of the mutations identified by Spelbrink et al. (2001) was a val368-to-ile (V368I) change, found in 2 Sicilian families with PEO. However, Arenas et al. (2003) reported that they found the same change in 1.2% of a normal control population and concluded that the change is a nonpathogenic polymorphism. A proband from 1 of the families with the mutation was later found to have mutations in the POLG gene (174763), which was presumably the disease-causing gene. </p><p>In a patient with sporadic PEO, Van Goethem et al. (2003) identified a heterozygous arg334-to-gln substitution in the C10ORF2 gene (R334Q; 606075.0008) cooccurring with a heterozygous gly848-to-ser mutation in the POLG gene (G848S; 174763.0006). Both mutations were absent in 180 Belgian control chromosomes. No mutations were found in the ANT1 gene (SLC25A4; 103220). </p><p>In 5 patients from 2 unrelated French families with autosomal dominant PEOA3, Echaniz-Laguna et al. (2010) identified a heterozygous mutation in the C10ORF2 gene (R374W; 606075.0014). Common features included ptosis, ophthalmoplegia, hearing loss, sensory axonal neuropathy, and proximal muscle weakness. The older patients, including deceased affected family members, developed abnormal gait, dysphagia, dysphonia, and late-onset dementia in their seventies and eighties. The findings expanded the phenotypic spectrum of PEOA3. </p><p><strong><em>Autosomal Recessive Mitochondrial DNA Depletion Syndrome 7 (Hepatocerebral Type)</em></strong></p><p>
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In Finnish patients with autosomal recessive mitochondrial DNA depletion syndrome-7 (MTDPS7; 271245), manifest as infantile-onset spinocerebellar ataxia (IOSCA), Nikali et al. (2005) identified homozygosity for a founder mutation in the C10ORF2 gene, Y508C (606075.0012). The phenotype was a severe neurodegenerative disorder characterized by progressive atrophy of the cerebellum, brainstem, and spinal cord and sensory axonal neuropathy, Hakonen et al. (2008) found that patients with the Y508C mutation had mtDNA depletion in brain tissue and liver. </p><p>In 2 Algerian sibs and a first cousin with autosomal recessive mitochondrial DNA deletion syndrome-7, Sarzi et al. (2007) identified a homozygous mutation in the C10ORF2 gene (606075.0011). All 3 patients were born of first-cousin parents and showed a severe hepatocerebral phenotype characterized by neonatal hypotonia, mild liver insufficiency, increased serum and CSF lactate, psychomotor retardation, seizures, and peripheral neuropathy. All 3 patients died by age 3 years. Mitochondrial DNA depletion was severe in 2 patients examined, with mtDNA levels in liver of 8% and 5% of normal, respectively. </p><p><strong><em>Perrault Syndrome 5</em></strong></p><p>
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In 4 women from 2 unrelated families with Perrault syndrome-5 (PRLTS5; 616138), Morino et al. (2014) identified compound heterozygous mutations in the C10ORF2 gene (606075.0016-606075.0019). The mutations, which were found by exome sequencing, segregated with the disorder in the families. All 4 mutations occurred in the helicase domain and were predicted to adversely affect enzyme activity based on structure, but functional studies of the variants were not performed. The patients presented as teenagers with primary amenorrhea and sensorineural hearing loss, and later developed ataxia and sensory axonal neuropathy. Morino et al. (2014) noted that the report expanded the phenotypic spectrum associated with recessive C10ORF2 mutations to include less severe neurologic involvement compared to MTDPS7 and a clinical presentation consistent with Perrault syndrome. </p><p><strong><em>Functional Studies of Mutant C10ORF2</em></strong></p><p>
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Longley et al. (2010) assayed the DNA-binding, DNA-unwinding, and ATPase activities of 20 different human p72 mutants, each containing a different amino acid substitution associated with mitochondrial disease. All 20 mutant forms exhibited helicase activity under the standard reaction conditions. Most substitutions altered DNA binding or the kinetics of ATP hydrolysis or helicase activity of the mutant protein, but none profoundly altered p72 function. </p><p>Peter et al. (2019) found that TWINKLE with PEOA3-associated mutations in the linker helix could form hexamers and heptamers, albeit at lower levels than wildtype. However, these mutations disrupted subunit flexibility, thereby reducing or eliminating TWINKLE catalytic activity. PEOA3-associated mutations in the TWINKLE primase domain, in close proximity to the primase-linker boundary, targeted the oligomerization process and caused structural and functional changes in TWINKLE. </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>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In a review of 29 pathogenic mutations in the C10ORF2 gene, Van Hove et al. (2009) found that all mutations clustered in a short region between residues arg303 and tyr508, involving the primase domains V and VI, the linker region, and the helicase domain. A phenotypic review of 56 patients with these mutations showed that most develop symptoms as adults between age 17 and 73 years. The most common symptoms were progressive external ophthalmoplegia and ptosis (96%). Almost half (46%) had symptoms of myopathy, usually described as limb-girdle, and 14% had a polyneuropathy. Other common features included brainstem symptoms (18%), depression (13%), and parkinsonism or tremors (13%), with less frequent features including diabetes mellitus, ataxia, cataract, memory loss, hearing loss, and cardiac problems. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Tyynismaa et al. (2004) reported that Twinkle expression patterns are not conserved between human and mouse but are synchronized with the adjacent gene Mrpl43, suggesting a shared promoter. The authors generated 2 transgenic mouse lines overexpressing wildtype Twinkle. Increased expression of Twinkle in muscle and heart increased mtDNA copy number up to 3-fold higher than controls, more than any other factor reported to date. In cultured human cells, reduced expression of Twinkle by RNA interference mediated a rapid drop in mtDNA copy number, further supporting the in vivo results. The authors concluded that Twinkle helicase is essential for mtDNA maintenance and that it may be a key regulator of mtDNA copy number in mammals. </p><p>Tyynismaa et al. (2005) generated transgenic mice overexpressing mouse Twinkle due to mutations corresponding to the PEO-associated mutations ala359 to thr (A359T; 606075.0003) and duplication of amino acids 352 to 364 (606075.0001) in humans. Multiple mtDNA deletions accumulated in the tissues of mutant mice, resulting in progressive respiratory dysfunction and chronic late-onset mitochondrial disease starting at 1 year of age. The muscles of mutant mice faithfully replicated features of PEO patients. These mice had progressive deficiency of cytochrome c oxidase in distinct neuronal populations, but they did not display premature aging. </p><p>Goffart et al. (2009) investigated the effects of dominant Twinkle PEO mutations in human cell culture and the Deletor mouse model, which expresses a dominant PEO mutation in Twinkle. Expression of dominant Twinkle mutations led to accumulation of mtDNA replication intermediates in cell culture. This indicated severe replication pausing or stalling and caused mtDNA depletion. Enhanced accumulation of replication intermediates was evident also in 6-week-old Deletor mice compared with wildtype littermates, even though mtDNA deletions accumulated in a late-onset fashion in this model. In vitro assays showed functional defects in the various Twinkle mutants and broadly agreed with the cell culture phenotypes such as the level of mtDNA depletion and the level of accumulation of replication intermediates. The authors suggested that mtDNA replication pausing or stalling is the common consequence of Twinkle PEO mutations that predisposes to multiple deletion formation. </p><p>Tyynismaa et al. (2010) studied the skeletal muscle gene expression profiles of mice with late-onset mitochondrial myopathy due to a dominant mutation in twinkle. The global gene expression pattern of the mouse skeletal muscle showed induction of pathways involved in amino acid starvation response and activation of Akt (164730) signaling. Furthermore, the muscle showed induction of a fasting-related hormone, fibroblast growth factor-21 (FGF21; 609436). Fgf21 was also elevated in the mouse serum, and the animals showed widespread changes in their lipid metabolism. The authors proposed that respiratory chain deficiency may induce a mitochondrial stress response, with local and global changes mimicking starvation, in a normal nutritional state, which may have important implications for understanding the metabolic consequences of mitochondrial myopathies. </p>
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</span>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>19 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 3</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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TWNK, 39-BP DUP
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<br />
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ClinVar: RCV000004879
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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 affected members of a Finnish family with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; 609286), originally reported by Suomalainen et al. (1992), Spelbrink et al. (2001) identified a 39-bp duplication (nucleotides 1053-1092) of the C10ORF2 gene, resulting in a duplication of amino acids 352-364 of twinkle. There was complete segregation of this duplication with the disease phenotype in this pedigree. The mutation was not identified in over 400 Finnish controls. Individuals with this duplication had severe retarded depression and avoidant personality features in addition to PEO. Three autopsies from family members showed the highest amounts of deleted mtDNA in the cerebral cortex and basal ganglia (approximately 60% of total mtDNA), followed by skeletal muscle and heart, with only small amounts in kidney. This distribution, however, did not correspond exactly with the pattern of twinkle expression, arguing for variable sensitivity of different tissues to twinkle dysfunction. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 3</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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TWNK, ALA475PRO
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<br />
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SNP: rs111033572,
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ClinVar: RCV000004880
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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 affected members of a Pakistani family reported by Li et al. (1999) with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; 609286), Spelbrink et al. (2001) identified a heterozygous 1423G-C transversion in the C10ORF2 gene, resulting in an ala475-to-pro (A475P) substitution. This mutation was not identified in 194 controls of various ethnic origin, including 88 of Pakistani/Indian origin. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 3</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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TWNK, ALA359THR
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<br />
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SNP: rs111033573,
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ClinVar: RCV000004881, RCV000508874, RCV002512779
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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 affected members of a large consanguineous Italian family segregating autosomal dominant progressive ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; 609286), Spelbrink et al. (2001) identified an ala359-to-thr (A359T) substitution in the twinkle protein. Two homozygous individuals had a more severe phenotype with earlier onset than their heterozygous relatives. This mutation was not detected in a control group of 100 individuals. </p><p>Longley et al. (2010) found that several disease-associated substitutions in p72, including A359T, which is located within the linker region, reduced the stability of the p72 hexamer. A359T also reduced p72 DNA-binding affinity and the velocities of p72 helicase and ATPase activities. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0004 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 3</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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TWNK, TRP474CYS
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<br />
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SNP: rs111033574,
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ClinVar: RCV000004882, RCV002496262
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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 affected members of a pedigree segregating autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; 609286), Spelbrink et al. (2001) identified a trp474-to-cys (W474C) substitution in the twinkle protein. This mutation was not identified in 100 controls. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 3</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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TWNK, TRP315LEU
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<br />
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|
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SNP: rs111033575,
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ClinVar: RCV000004883
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In affected members of a pedigree segregating autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; 609286), Spelbrink et al. (2001) identified a trp315-to-leu (W315L) substitution in the twinkle protein. This mutation was in a moderately conserved segment of the linker region and was not identified in 100 controls. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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TWNK, ARG354PRO
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<br />
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|
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SNP: rs111033576,
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|
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gnomAD: rs111033576,
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|
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ClinVar: RCV000004884
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|
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|
|
</span>
|
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</div>
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of an Italian family segregating autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; 609286), Spelbrink et al. (2001) identified a 1061G-C transversion in the C10ORF2 gene, resulting in an arg354-to-pro (R354P) substitution. This mutation was not identified in 100 normal controls. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
TWNK, LEU381PRO
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|
|
<br />
|
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|
|
SNP: rs111033577,
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|
|
ClinVar: RCV000004885, RCV000508905
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|
|
|
|
|
</span>
|
|
</div>
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of an Italian family segregating autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; 609286), Spelbrink et al. (2001) identified a 1442T-C transition in the C10ORF2 gene, resulting in a leu381-to-pro (L381P) substitution. This mutation segregated strictly with the disease in this family and was not identified in 100 controls. </p><p>Longley et al. (2010) found that several disease-associated substitutions in p72, including L381P, which is located between the linker region and helicase domain, reduced the stability of the p72 hexamer. L381P also increased the rate of ATP hydrolysis by p72 over that measured for wildtype p72. However, elevated ATP hydrolysis was not accompanied by proportionately higher DNA helicase activity, implying that nucleotide hydrolysis and DNA translocation may be partially uncoupled by the L381P substitution. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, DIGENIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TWNK, ARG334GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28937887,
|
|
|
|
|
|
|
|
ClinVar: RCV000004886, RCV000508769, RCV001093424, RCV001542762, RCV002288465
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a sporadic case of progressive external ophthalmoplegia (see 609286 and 157640), Van Goethem et al. (2003) identified heterozygosity for a 1031G-A transition in the C10ORF2 gene, resulting in an arg334-to-gln (R334Q) mutation, and heterozygosity for a gly884-to-ser mutation in the POLG gene (G884S; 174763.0006), indicating a digenic mode of inheritance. Clinical onset in the patient was at 52 years of age with blepharoptosis, depression, and levodopa-responsive Parkinson disease. Later she suffered from severe dysphagia leading to cachexia and necessitating enteric feeding. Sudden death, attributed to cardiac arrest, occurred at age 66 years. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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|
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|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TWNK, SER369TYR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs111033579,
|
|
|
|
|
|
gnomAD: rs111033579,
|
|
|
|
|
|
ClinVar: RCV000004887
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a large family with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; 609286), Lewis et al. (2002) identified a heterozygous 1106C-A transversion in the C10ORF2 gene, resulting in a ser369-to-tyr (S369Y) substitution in the linker region of the protein. Affected members of a second presumably unrelated family were found to have the same mutation. Both families originated from the same region in Tasmania, and haplotype analysis showed a common haplotype. The S369Y mutation was not identified in 100 control individuals. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
TWNK, LYS319GLU
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|
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<br />
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|
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SNP: rs80356543,
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|
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ClinVar: RCV000004888, RCV000020867
|
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|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs with autosomal dominant progressive external ophthalmoplegia with mitochondrial deletions-3 (PEOA3; 609286), Hudson et al. (2005) identified a heterozygous 955A-G transition in the C10ORF2 gene, resulting in a lys319-to-glu (K319E) substitution. The 45-year-old proband had ptosis, external ophthalmoplegia, moderate proximal weakness of the legs, severe sensory ataxia, and moderate dementia. His sister had ptosis, ophthalmoplegia, proximal leg weakness, dysarthria, ataxia, and signs of a sensory neuropathy. She subsequently developed dementia, diabetes, and seizures. At age 41 she developed status epilepticus and died. The mutation was not identified in the parents' blood, hair follicles, buccal mucosa, or urinary epithelium, indicating germline mosaicism. Hudson et al. (2005) emphasized that the findings broadened the phenotype associated with C10ORF2 mutations, and noted the phenotypic overlap with sensory ataxia neuropathy, dysarthria, and ophthalmoparesis (SANDO; 607459), The authors also noted that the mutation caused the replacement of a basic amino acid with an acidic amino acid in a conserved region of the protein, which may have accounted for the more severe phenotype observed in their patients compared to other patients with C10ORF2 mutations. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 MITOCHONDRIAL DNA DEPLETION SYNDROME 7 (HEPATOCEREBRAL TYPE)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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TWNK, THR457ILE
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<br />
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SNP: rs80356544,
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gnomAD: rs80356544,
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ClinVar: RCV000004889
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In 2 Algerian sibs and a first cousin with autosomal recessive mitochondrial DNA depletion syndrome-7 (MTDPS7; 271245), Sarzi et al. (2007) identified a homozygous 1370C-T transition in the C10ORF2 gene, resulting in a thr457-to-ile (T457I) substitution. All 3 patients were born of first-cousin parents and showed a severe hepatocerebral phenotype characterized by neonatal hypotonia, mild liver insufficiency, increased serum and CSF lactate, psychomotor retardation, seizures, and peripheral neuropathy. All 3 patients died by age 3 years. Mitochondrial DNA depletion was severe in 2 patients examined, with mtDNA levels in liver of 8% and 5% of normal, respectively. Molecular modeling predicted that the mutation is located in the interface between 2 monomers of the hexameric enzyme. In vitro functional expression studies showed that the T457I mutant protein had a more than 50% reduction in helicase activity. Family members who were presumed obligate carriers were unaffected. </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>.0012 MITOCHONDRIAL DNA DEPLETION SYNDROME 7 (HEPATOCEREBRAL TYPE)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TWNK, TYR508CYS
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|
<br />
|
|
|
|
SNP: rs80356540,
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|
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|
|
|
gnomAD: rs80356540,
|
|
|
|
|
|
ClinVar: RCV000020865, RCV000199894
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In Finnish patients with mitochondrial DNA depletion syndrome-7 (MTDPS7; 271245) manifest as infantile-onset autosomal recessive spinocerebellar ataxia, Nikali et al. (2005) identified homozygosity for a founder mutation in exon 3 of the C10ORF2 gene: a 1708A-G transition resulting in a tyr508-to-cys (Y508C) substitution in the twinkle and twinky proteins. One other Finnish patient was compound heterozygous for Y508C inherited from his mother and a silent mutation (1472C-T) in exon 2 of C10ORF2 inherited from his father that affected allelic expression levels. Carrier frequency for the mutation peaked at approximately 2.5% in south central Finland. The Y508C mutation was not found in unaffected family members, 712 Finnish control samples, or 95 non-Finnish controls; the silent mutation was not found in 207 Finnish or 95 foreign controls. </p>
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</span>
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</div>
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<div>
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<br />
|
|
</div>
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|
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</div>
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|
|
<div>
|
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
TWNK, ARG303GLN
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<br />
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|
|
SNP: rs137852956,
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|
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|
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gnomAD: rs137852956,
|
|
|
|
|
|
ClinVar: RCV000004891, RCV001289123
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 71-year-old woman who developed autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; 609286) at age 51, Van Hove et al. (2009) identified a heterozygous 908G-A transition in exon 1 of the TWNK gene, resulting in an arg303-to-gln (R303Q) substitution in the first amino acid of primase motif V. The mutation was not found in 250 control chromosomes. Other clinical features included cataracts, adult-onset diabetes mellitus, distal paresthesias, sensorineural hearing loss, mild sensory ataxia, and chronic progressive limb-girdle muscle weakness. Brain MRI showed scattered white matter changes in the subcortical and periventricular regions. Skeletal muscle biopsy showed a few ragged-red fibers and multiple mtDNA deletions. </p>
|
|
</span>
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</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>.0014 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TWNK, ARG374TRP
|
|
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|
|
|
<br />
|
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|
|
SNP: rs267606682,
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|
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|
|
|
gnomAD: rs267606682,
|
|
|
|
|
|
ClinVar: RCV000004892, RCV000523637
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 patients from 2 unrelated French families with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOA3; 609286), Echaniz-Laguna et al. (2010) identified a heterozygous 1120C-T transition in the C10ORF2 gene, resulting in an arg374-to-trp (R374W) substitution in the linker region. Common features included ptosis, ophthalmoplegia, hearing loss, sensory axonal neuropathy, and proximal muscle weakness. The older patients, including deceased affected family members, developed abnormal gait, dysphagia, dysphonia, and late-onset dementia in their seventies and eighties. </p>
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
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|
|
<div>
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 MITOCHONDRIAL DNA DEPLETION SYNDROME 7 (HEPATOCEREBRAL TYPE)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TWNK, ALA318THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80356542,
|
|
|
|
|
|
gnomAD: rs80356542,
|
|
|
|
|
|
ClinVar: RCV000020866, RCV002251876
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 Finnish sibs with mtDNA depletion syndrome-7 (MTDPS7; 271245), manifest as infantile-onset spinocerebellar ataxia, Hakonen et al. (2007) identified compound heterozygosity for 2 mutations in the C10ORF2 gene: a 952G-A transition, resulting in an ala318-to-thr (A318T) substitution, and the Y508C mutation (606075.0012). The phenotype was severe, showing hypotonia, athetosis, sensory neuropathy, ataxia, hearing deficit, ophthalmoplegia, and refractory epilepsy. The older sib died at age 4.5 years of status epilepticus. One patient had mtDNA depletion in the liver. Each unaffected parent was heterozygous for 1 of the mutations. The A318T mutation was not present in 120 Finnish control chromosomes. Hakonen et al. (2007) noted that the phenotype was reminiscent of Alpers syndrome (MTDPS4B; 203700), which is caused by mutation in the POLG gene (174763). </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 PERRAULT SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TWNK, ARG391HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs556445621,
|
|
|
|
|
|
gnomAD: rs556445621,
|
|
|
|
|
|
ClinVar: RCV000149470, RCV000290037, RCV000305281, RCV000345001, RCV000403533, RCV002516005, RCV002516006
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 Japanese sisters with Perrault syndrome-5 (PRLTS5; 616138), Morino et al. (2014) identified compound heterozygous mutations in the C10ORF2 gene: a c.1172G-A transition resulting in an arg391-to-his (R391H) substitution at a less conserved residue, and a c.1754A-G transition resulting in an asn585-to-ser (N585S; 606075.0017) substitution at a conserved residue. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variants were filtered against the dbSNP (build 137), 1000 Genomes Project, and Exome Sequencing Project databases and were absent from in-house control exomes. Both mutations occurred in the helicase domain and were predicted to adversely affect enzyme activity based on structure, but functional studies of the variants were not performed. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 PERRAULT SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TWNK, ASN585SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs672601360,
|
|
|
|
|
|
gnomAD: rs672601360,
|
|
|
|
|
|
ClinVar: RCV000149471, RCV002514865, RCV003556196
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the asn585-to-ser (N585S) mutation in the C10ORF2 gene that was found in 2 sisters with Perrault syndrome-5 (PRLTS5; 616138) by Morino et al. (2014), see 606075.0016. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 PERRAULT SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TWNK, TRP441GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs672601361,
|
|
|
|
|
|
gnomAD: rs672601361,
|
|
|
|
|
|
ClinVar: RCV000149472, RCV002516007, RCV003556197
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sisters of paternal Greek ancestry and maternal mixed European ancestry with Perrault syndrome-5 (PRLTS5; 616138), Morino et al. (2014) identified compound heterozygous mutations in the C10ORF2 gene: a c.1321T-G transversion resulting in a trp441-to-gly (W441G) substitution at a conserved residue, and a c.1519G-A transition resulting in a val507-to-ile (V507I; 606075.0019) substitution at a less well-conserved residue. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variants were filtered against the dbSNP (build 137), 1000 Genomes Project, and Exome Sequencing Project databases and were absent from in-house control exomes: V507I was found once in the Exome Sequencing Project database. Both mutations occurred in the helicase domain and were predicted to adversely affect enzyme activity based on structure, but functional studies of the variants were not performed. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 PERRAULT SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TWNK, VAL507ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs369588002,
|
|
|
|
|
|
gnomAD: rs369588002,
|
|
|
|
|
|
ClinVar: RCV000149473, RCV000521090, RCV002514866, RCV003479021
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the val507-to-ile (V507I) mutation in the C10ORF2 gene that was found in 2 sisters with Perrault syndrome-5 (PRLTS5; 616138) by Morino et al. (2014), see 606075.0018. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Arenas, J., Briem, E., Dahl, H., Hutchison, W., Lewis, S., Martin, M. A., Spelbrink, H., Tiranti, V., Jacobs, H., Zeviani, M.
|
|
<strong>The V368I mutation in twinkle does not segregate with adPEO. (Letter)</strong>
|
|
Ann. Neurol. 53: 278 only, 2003.
|
|
|
|
|
|
[PubMed: 12557300]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ana.10430]
|
|
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|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Echaniz-Laguna, A., Chanson, J. B., Wilhelm, J. M., Sellal, F., Mayencon, M., Mohr, M., Tranchant, C., de Camaret, B. M.
|
|
<strong>A novel variation in the Twinkle linker region causing late-onset dementia.</strong>
|
|
Neurogenetics 11: 21-25, 2010.
|
|
|
|
|
|
[PubMed: 19513767]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s10048-009-0202-4]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Farge, G., Holmlund, T., Khvorostova, J., Rofougaran, R., Hofer, A., Falkenberg, M.
|
|
<strong>The N-terminal domain of TWINKLE contributes to single-stranded DNA binding and DNA helicase activities.</strong>
|
|
Nucleic Acids Res. 36: 393-403, 2008.
|
|
|
|
|
|
[PubMed: 18039713]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/nar/gkm1025]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Goffart, S., Cooper, H. M., Tyynismaa, H., Wanrooij, S., Suomalainen, A., Spelbrink, J. N.
|
|
<strong>Twinkle mutations associated with autosomal dominant progressive external ophthalmoplegia lead to impaired helicase function and in vivo mtDNA replication stalling.</strong>
|
|
Hum. Molec. Genet. 18: 328-340, 2009.
|
|
|
|
|
|
[PubMed: 18971204]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddn359]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hakonen, A. H., Goffart, S., Marjavaara, S., Paetau, A., Cooper, H., Mattila, K., Lampinen, M., Sajantila, A., Lonnqvist, T., Spelbrink, J. N., Suomalainen, A.
|
|
<strong>Infantile-onset spinocerebellar ataxia and mitochondrial recessive ataxia syndrome are associated with neuronal complex I defect and mtDNA depletion.</strong>
|
|
Hum. Molec. Genet. 17: 3822-3835, 2008.
|
|
|
|
|
|
[PubMed: 18775955]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddn280]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hakonen, A. H., Isohanni, P., Paetau, A., Herva, R., Suomalainen, A., Lonnqvist, T.
|
|
<strong>Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion.</strong>
|
|
Brain 130: 3032-3040, 2007.
|
|
|
|
|
|
[PubMed: 17921179]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/brain/awm242]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Hudson, G., Deschauer, M., Busse, K., Zierz, S., Chinnery, P. F.
|
|
<strong>Sensory ataxic neuropathy due to a novel C10ORF2 mutation with probable germline mosaicism.</strong>
|
|
Neurology 64: 371-373, 2005.
|
|
|
|
|
|
[PubMed: 15668446]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1212/01.WNL.0000149767.51152.83]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lewis, S., Hutchison, W., Thyagarajan, D., Dahl, H.-H. M.
|
|
<strong>Clinical and molecular features of adPEO due to mutations in the twinkle gene.</strong>
|
|
J. Neurol. Sci. 201: 39-44, 2002.
|
|
|
|
|
|
[PubMed: 12163192]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s0022-510x(02)00190-9]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Li, F. Y., Tariq, M., Croxen, R., Morten, K., Squier, W., Newsom-Davis, J., Beeson, D., Larsson, C.
|
|
<strong>Mapping of autosomal dominant progressive external ophthalmoplegia to a 7-cM critical region on 10q24.</strong>
|
|
Neurology 53: 1265-1271, 1999.
|
|
|
|
|
|
[PubMed: 10522883]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1212/wnl.53.6.1265]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Longley, M. J., Humble, M. M., Sharief, F. S., Copeland, W. C.
|
|
<strong>Disease variants of the human mitochondrial DNA helicase encoded by C10orf2 differentially alter protein stability, nucleotide hydrolysis, and helicase activity.</strong>
|
|
J. Biol. Chem. 285: 29690-29702, 2010.
|
|
|
|
|
|
[PubMed: 20659899]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1074/jbc.M110.151795]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Morino, H., Pierce, S. B., Matsuda, Y., Walsh, T., Ohsawa, R., Newby, M., Hiraki-Kamon, K., Kuramochi, M., Lee, M. K., Klevit, R. E., Martin, A., Maruyama, H., King, M.-C., Kawakami, H.
|
|
<strong>Mutations in Twinkle primase-helicase cause Perrault syndrome with neurologic features.</strong>
|
|
Neurology 83: 2054-2061, 2014.
|
|
|
|
|
|
[PubMed: 25355836]
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Peter, B., Farge, G., Pardo-Hernandez, C., Tangefjord, S., Falkenberg, M.
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<strong>Structural basis for adPEO-causing mutations in the mitochondrial TWINKLE helicase.</strong>
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Sen, D., Nandakumar, D., Tang, G.-Q., Patel, S. S.
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<strong>Human mitochondrial DNA helicase TWINKLE is both an unwinding and annealing helicase.</strong>
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Spelbrink, J. N., Li, F.-Y., Tiranti, V., Nikali, K., Yuan, Q.-P., Tariq, M., Wanrooij, S., Garrido, N., Comi, G., Morandi, L., Santoro, L., Toscano, A., and 9 others.
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<strong>Human mitochondrial DNA deletions associated with mutations in the gene encoding twinkle, a phage T7 gene 4-like protein localized in mitochondria.</strong>
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Suomalainen, A., Majander, A., Haltia, M., Somer, H., Lonnqvist, J., Savontaus, M.-L., Peltonen, L.
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<strong>Multiple deletions of mitochondrial DNA in several tissues of a patient with severe retarded depression and familial progressive external ophthalmoplegia.</strong>
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J. Clin. Invest. 90: 61-66, 1992.
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Tyynismaa, H., Carroll, C. J., Raimundo, N., Ahola-Erkkila, S., Wenz, T., Ruhanen, H., Guse, K., Hemminki, A., Peltola-Mjosund, K. E., Tulkki, V., Oresic, M., Moraes, C. T., Pietilainen, K., Hovatta, I., Suomalainen, A.
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<strong>Mitochondrial myopathy induces a starvation-like response.</strong>
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Tyynismaa, H., Mjosund, K. P., Wanrooij, S., Lappalainen, I., Ylikallio, E., Jalanko, A., Spelbrink, J. N., Paetau, A., Suomalainen, A.
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<strong>Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice.</strong>
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Tyynismaa, H., Sembongi, H., Bokori-Brown, M., Granycome, C., Ashley, N., Poulton, J., Jalanko, A., Spelbrink, J. N., Holt, I. J., Suomalainen, A.
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<strong>Twinkle helicase is essential for mtDNA maintenance and regulates mtDNA copy number.</strong>
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Van Goethem, G., Lofgren, A., Dermaut, B., Ceuterick, C., Martin, J.-J., Van Broeckhoven, C.
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<strong>Digenic progressive external ophthalmoplegia in a sporadic patient: recessive mutations in POLG and C10orf2/Twinkle. (Letter)</strong>
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Van Hove, J. L. K., Cunningham, V., Rice, C., Ringel, S. P., Zhang, Q., Chou, P.-C., Truong, C. K., Wong, L.-J. C.
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<strong>Finding twinkle in the eyes of a 71-year-old lady: A case report and review of the genotypic and phenotypic spectrum of TWINKLE-related dominant disease.</strong>
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