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- *516006 - COMPLEX I, SUBUNIT ND6; MTND6
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- OMIM
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<p>
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<span class="h4">*516006</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</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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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<a href="/allelicVariants/516006">Table View</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000198695;t=-" 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://mitomap.org/bin/view.pl/Main/SearchSite?search=MT-ND6" class="mim-tip-hint" title="A curated repository of published and unpublished data on human mitochondrial DNA variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MITOMAP', 'domain': 'mitomap.org'})">MITOMAP</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=4541" 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=516006" 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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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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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=ENSG00000198695;t=-" 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</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=516006" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="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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<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://www.proteinatlas.org/search/MT-ND6" 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/2052367,6648060,251831118" 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/P03923" 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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<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=4541" 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=ENSG00000198695;t=-" 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=MT-ND6" 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=MT-ND6" 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+4541" 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/MT-ND6" 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:4541" 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/4541" 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>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:7462" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/mt-nd6" 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=516006[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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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=516006[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/ENSG00000198695" 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.gwascentral.org/search?q=MT-ND6" 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=MT-ND6" 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=MT-ND6&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/PA31266" 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 class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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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 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><a href="https://www.alliancegenome.org/gene/HGNC:7462" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:102495" 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/MT-ND6#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:102495" 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/4541/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=4541" 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 style="display: table-cell;">Cellular Pathways</div>
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:4541" 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=MT-ND6&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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<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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<a id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 39925003, 58610003, 89439007<br />
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<strong>ICD10CM:</strong> E88.41, H47.22<br />
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">ICD+</a>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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516006
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<a id="preferredTitle" class="mim-anchor"></a>
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COMPLEX I, SUBUNIT ND6; MTND6
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<div>
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<br />
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<span class="mim-font">
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NADH-UBIQUINONE OXIDOREDUCTASE, SUBUNIT ND6<br />
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NADH DEHYDROGENASE, SUBUNIT 6
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<br />
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=MT-ND6" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">MT-ND6</a></em></strong>
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<h4>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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<div>
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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<div id="mimDescriptionFold" class="collapse in ">
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<p>Subunit 6 is 1 of the 7 mitochondrial DNA (mtDNA) encoded subunits (MTND1, MTND2, MTND3, MTND4L, MTND4, MTND5, MTND6) included among the approximately 41 polypeptides of respiratory Complex I (NADH:ubiquinone oxidoreductase, <a href="https://enzyme.expasy.org/EC/1.6.5.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 1.6.5.3</a>) (<a href="#39" class="mim-tip-reference" title="Shoffner, J. M., Wallace, D. C. <strong>Oxidative phosphorylation diseases.In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.) : The Metabolic and Molecular Bases of Inherited Disease. Vol. 1.</strong> New York: McGraw-Hill (pub.) 1995. Pp. 1535-1609."None>Shoffner and Wallace, 1995</a>; <a href="#2" class="mim-tip-reference" title="Arizmendi, J. M., Skehel, J. M., Runswick, M. J., Fearnley, I. M., Walker, J. E. <strong>Complementary DNA sequences of two 14.5 kDa subunits of NADH:ubiquinone oxidoreductase from bovine heart mitochondria. Complementation of the primary structure of the complex.</strong> FEBS Lett. 313: 80-84, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1426273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1426273</a>] [<a href="https://doi.org/10.1016/0014-5793(92)81189-s" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1426273">Arizmendi et al., 1992</a>; <a href="#44" class="mim-tip-reference" title="Walker, J. E., Arizmendi, J. M., Dupuis, A., Fearnley, I. M., Finel, M., Medd, S. M., Pilkington, S. J., Runswick, M. J., Skehel, J. M. <strong>Sequences of 20 subunits of NADH:ubiquinone oxidoreductase from bovine heart mitochondria: application of a novel strategy for sequencing proteins using the polymerase chain reaction.</strong> J. Molec. Biol. 226: 1051-1072, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1518044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1518044</a>] [<a href="https://doi.org/10.1016/0022-2836(92)91052-q" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1518044">Walker et al., 1992</a>; <a href="#1" class="mim-tip-reference" title="Anderson, S., Bankier, A. T., Barrell, B. G., de Bruijn, M. H. L., Coulson, A. R., Drouin, J., Eperon, I. C., Nierlich, D. P., Roe, B. A., Sanger, F., Schreier, P. H., Smith, A. J. H., Staden, R., Young, I. G. <strong>Sequence and organization of the human mitochondrial genome.</strong> Nature 290: 457-465, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7219534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7219534</a>] [<a href="https://doi.org/10.1038/290457a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7219534">Anderson et al., 1981</a>; <a href="#3" class="mim-tip-reference" title="Attardi, G., Chomyn, A., Doolittle, R. F., Mariottini, P., Ragan, C. I. <strong>Seven unidentified reading frames of human mitochondrial DNA encode subunits of the respiratory chain NADH dehydrogenase.</strong> Cold Spring Harbor Symp. Quant. Biol. 51: 103-114, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3472707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3472707</a>] [<a href="https://doi.org/10.1101/sqb.1986.051.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3472707">Attardi et al., 1986</a>; Chomyn et al. (<a href="#14" class="mim-tip-reference" title="Chomyn, A., Mariottini, P., Cleeter, M. W. J., Ragan, C. I., Matsuno-Yagi, A., Hatefi, Y., Doolittle, R. G., Attardi, G. <strong>Six unidentified reading frames of human mitochondrial DNA encode components of the respiratory-chain NADH dehydrogenase.</strong> Nature 314: 592-597, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3921850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3921850</a>] [<a href="https://doi.org/10.1038/314592a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3921850">1985</a>, <a href="#13" class="mim-tip-reference" title="Chomyn, A., Cleeter, W. J., Ragan, C. I., Riley, M., Doolittle, R. F., Attardi, G. <strong>URF6, last unidentified reading frame of human mtDNA, codes for an NADH dehydrogenase subunit.</strong> Science 234: 614-618, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3764430/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3764430</a>] [<a href="https://doi.org/10.1126/science.3764430" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3764430">1986</a>); <a href="#46" class="mim-tip-reference" title="Wallace, D. C., Yang, J., Ye, J., Lott, M. T., Oliver, N. A., McCarthy, J. <strong>Computer prediction of peptide maps: Assignment of polypeptides to human and mouse mitochondrial DNA genes by analysis of two-dimensional-proteolytic digest gels.</strong> Am. J. Hum. Genet. 38: 461, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3518425/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3518425</a>]" pmid="3518425">Wallace et al., 1986</a>; <a href="#34" class="mim-tip-reference" title="Oliver, N. A., Wallace, D. C. <strong>Assignment of two mitochondrially synthesized polypeptides to human mitochondrial DNA and their use in the study of intracellular mitochondrial interaction.</strong> Molec. Cell. Biol. 2: 30-41, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6955589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6955589</a>] [<a href="https://doi.org/10.1128/mcb.2.1.30-41.1982" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6955589">Oliver and Wallace, 1982</a>; <a href="#45" class="mim-tip-reference" title="Wallace, D. C., Lott, M. T., Torroni, A., Brown, M. D., Shoffner, J. M. <strong>Report of the committee on human mitochondrial DNA.In: Cuticchia, A. J.; Pearson, P. L. (eds.) : Human Gene Mapping, 1993: A Compendium.</strong> Baltimore: Johns Hopkins Univ. Press (pub.) 1994. Pp. 813-845."None>Wallace et al., 1994</a>). Complex I accepts electrons from NADH, transfers them to ubiquinone (Coenzyme Q10), and uses the energy released to pump protons across the mitochondria inner membrane. Complex I is more fully described under <a href="/entry/516000">516000</a>. MTND6 has been proposed to be a component of the iron-protein fragment (<a href="#13" class="mim-tip-reference" title="Chomyn, A., Cleeter, W. J., Ragan, C. I., Riley, M., Doolittle, R. F., Attardi, G. <strong>URF6, last unidentified reading frame of human mtDNA, codes for an NADH dehydrogenase subunit.</strong> Science 234: 614-618, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3764430/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3764430</a>] [<a href="https://doi.org/10.1126/science.3764430" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3764430">Chomyn et al., 1986</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3518425+1426273+3472707+3764430+3921850+7219534+6955589+1518044" 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>The predicted polypeptide has a molecular weight of 18.6 kD (<a href="#1" class="mim-tip-reference" title="Anderson, S., Bankier, A. T., Barrell, B. G., de Bruijn, M. H. L., Coulson, A. R., Drouin, J., Eperon, I. C., Nierlich, D. P., Roe, B. A., Sanger, F., Schreier, P. H., Smith, A. J. H., Staden, R., Young, I. G. <strong>Sequence and organization of the human mitochondrial genome.</strong> Nature 290: 457-465, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7219534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7219534</a>] [<a href="https://doi.org/10.1038/290457a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7219534">Anderson et al., 1981</a>). However, its apparent MW on SDS-polyacrylamide gels (PAGE) using Tris-glycine buffer is 16.7 kD (<a href="#33" class="mim-tip-reference" title="Oliver, N. A., McCarthy, J., Wallace, D. C. <strong>Comparison of mitochondrially synthesized polypeptides of human, mouse, and monkey cell lines by a two-dimensional protease gel system.</strong> Somat. Cell Molec. Genet. 10: 639-643, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6438810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6438810</a>] [<a href="https://doi.org/10.1007/BF01535230" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6438810">Oliver et al., 1984</a>; <a href="#34" class="mim-tip-reference" title="Oliver, N. A., Wallace, D. C. <strong>Assignment of two mitochondrially synthesized polypeptides to human mitochondrial DNA and their use in the study of intracellular mitochondrial interaction.</strong> Molec. Cell. Biol. 2: 30-41, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6955589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6955589</a>] [<a href="https://doi.org/10.1128/mcb.2.1.30-41.1982" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6955589">Oliver and Wallace, 1982</a>; <a href="#46" class="mim-tip-reference" title="Wallace, D. C., Yang, J., Ye, J., Lott, M. T., Oliver, N. A., McCarthy, J. <strong>Computer prediction of peptide maps: Assignment of polypeptides to human and mouse mitochondrial DNA genes by analysis of two-dimensional-proteolytic digest gels.</strong> Am. J. Hum. Genet. 38: 461, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3518425/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3518425</a>]" pmid="3518425">Wallace et al., 1986</a>), and the apparent MW on urea-phosphate gels is also close to the predicted molecular weight (<a href="#13" class="mim-tip-reference" title="Chomyn, A., Cleeter, W. J., Ragan, C. I., Riley, M., Doolittle, R. F., Attardi, G. <strong>URF6, last unidentified reading frame of human mtDNA, codes for an NADH dehydrogenase subunit.</strong> Science 234: 614-618, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3764430/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3764430</a>] [<a href="https://doi.org/10.1126/science.3764430" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3764430">Chomyn et al., 1986</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3518425+3764430+7219534+6955589+6438810" 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>MTND6 is encoded by the cytosine-rich light (L) strand of the mtDNA and located between nucleotide pairs (nps) 14149 and 14673 (<a href="#1" class="mim-tip-reference" title="Anderson, S., Bankier, A. T., Barrell, B. G., de Bruijn, M. H. L., Coulson, A. R., Drouin, J., Eperon, I. C., Nierlich, D. P., Roe, B. A., Sanger, F., Schreier, P. H., Smith, A. J. H., Staden, R., Young, I. G. <strong>Sequence and organization of the human mitochondrial genome.</strong> Nature 290: 457-465, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7219534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7219534</a>] [<a href="https://doi.org/10.1038/290457a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7219534">Anderson et al., 1981</a>; <a href="#45" class="mim-tip-reference" title="Wallace, D. C., Lott, M. T., Torroni, A., Brown, M. D., Shoffner, J. M. <strong>Report of the committee on human mitochondrial DNA.In: Cuticchia, A. J.; Pearson, P. L. (eds.) : Human Gene Mapping, 1993: A Compendium.</strong> Baltimore: Johns Hopkins Univ. Press (pub.) 1994. Pp. 813-845."None>Wallace et al., 1994</a>). It is maternally inherited along with the mtDNA (<a href="#19" class="mim-tip-reference" title="Giles, R. E., Blanc, H., Cann, H. M., Wallace, D. C. <strong>Maternal inheritance of human mitochondrial DNA.</strong> Proc. Nat. Acad. Sci. 77: 6715-6719, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6256757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6256757</a>] [<a href="https://doi.org/10.1073/pnas.77.11.6715" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6256757">Giles et al., 1980</a>; <a href="#11" class="mim-tip-reference" title="Case, J. T., Wallace, D. C. <strong>Maternal inheritance of mitochondrial DNA polymorphisms in cultured human fibroblasts.</strong> Somat. Cell Genet. 7: 103-108, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6261411/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6261411</a>] [<a href="https://doi.org/10.1007/BF01544751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6261411">Case and Wallace, 1981</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7219534+6261411+6256757" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The MTND6 polypeptide encompasses 524 nps of continuous coding sequence. The gene contains no introns, begins with the AUG methionine start codon and ends with a UCG codon which has been proposed as the stop signal. The mRNA has a 3-prime noncoding sequence which includes 1811 nps corresponding to the anti-sense of the MTND5 coding sequence and may also extend through the tRNALeu(CUN), tRNASer(AGY), tRNAHis, and MTND4 genes, ending at tRNAArg. It is transcribed as a part of the large polycistronic L-strand transcript and is flanked on the 5-prime end by the tRNAGlu. Processing occurs at tRNAGlu and tRNAArg to give the stable L-strand transcript 3 (<a href="#1" class="mim-tip-reference" title="Anderson, S., Bankier, A. T., Barrell, B. G., de Bruijn, M. H. L., Coulson, A. R., Drouin, J., Eperon, I. C., Nierlich, D. P., Roe, B. A., Sanger, F., Schreier, P. H., Smith, A. J. H., Staden, R., Young, I. G. <strong>Sequence and organization of the human mitochondrial genome.</strong> Nature 290: 457-465, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7219534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7219534</a>] [<a href="https://doi.org/10.1038/290457a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7219534">Anderson et al., 1981</a>; <a href="#32" class="mim-tip-reference" title="Ojala, D., Montoya, J., Attardi, G. <strong>tRNA punctuation model of RNA processing in human mitochondria.</strong> Nature 290: 470-474, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7219536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7219536</a>] [<a href="https://doi.org/10.1038/290470a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7219536">Ojala et al., 1981</a>; <a href="#4" class="mim-tip-reference" title="Attardi, G., Chomyn, A., Montoya, J., Ojala, D. <strong>Identification and mapping of human mitochondrial genes.</strong> Cytogenet. Cell Genet. 32: 85-98, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7140372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7140372</a>] [<a href="https://doi.org/10.1159/000131689" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7140372">Attardi et al., 1982</a>; <a href="#30" class="mim-tip-reference" title="Montoya, J., Ojala, D., Attardi, G. <strong>Distinctive features of the 5'-terminal sequences of the human mitochondrial mRNAs.</strong> Nature 290: 465-470, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7219535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7219535</a>] [<a href="https://doi.org/10.1038/290465a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7219535">Montoya et al., 1981</a>; <a href="#45" class="mim-tip-reference" title="Wallace, D. C., Lott, M. T., Torroni, A., Brown, M. D., Shoffner, J. M. <strong>Report of the committee on human mitochondrial DNA.In: Cuticchia, A. J.; Pearson, P. L. (eds.) : Human Gene Mapping, 1993: A Compendium.</strong> Baltimore: Johns Hopkins Univ. Press (pub.) 1994. Pp. 813-845."None>Wallace et al., 1994</a>). Further processing at tRNALeu(CUN) could give a mRNA equivalent in length to the H-strand transcript 5 for MTND5. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7219534+7140372+7219535+7219536" 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="#41" class="mim-tip-reference" title="Temperley, R., Richter, R. Dennerlein, S., Lightowlers, R. N., Chrzanowska-Lightowlers, Z. M. <strong>Hungry codons promote frameshifting in human mitochondrial ribosomes.</strong> Science 327: 301 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20075246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20075246</a>] [<a href="https://doi.org/10.1126/science.1180674" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20075246">Temperley et al. (2010)</a> demonstrated that human mitoribosomes do invoke -1 frameshift at the AGA and AGG codons predicted to terminate the 2 ORFs in MTCO1 (<a href="/entry/516030">516030</a>) and MTND6, respectively. As a consequence, both ORFs terminate in the standard UAG codon, necessitating the use of only a single mitochondrial release factor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20075246" 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>Restriction site polymorphisms have been identified at the following nucleotide position for the indicated enzymes (where '+' = site gain, '-' = site loss relative to the reference sequence, <a href="#1" class="mim-tip-reference" title="Anderson, S., Bankier, A. T., Barrell, B. G., de Bruijn, M. H. L., Coulson, A. R., Drouin, J., Eperon, I. C., Nierlich, D. P., Roe, B. A., Sanger, F., Schreier, P. H., Smith, A. J. H., Staden, R., Young, I. G. <strong>Sequence and organization of the human mitochondrial genome.</strong> Nature 290: 457-465, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7219534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7219534</a>] [<a href="https://doi.org/10.1038/290457a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7219534">Anderson et al., 1981</a>): Alu I: -14304, +14322, +14509; BamHI: -14258; Dde I: +14385, +14394, -14608; Hae III: +14279; HincII: -14199, +14648/15765; HinfI: +14268, -14368; Mbo I: -14259, +14279; Msp I: +14567;; Rsa I: +14347; Taq I: +14050/14366, +14168 (<a href="#45" class="mim-tip-reference" title="Wallace, D. C., Lott, M. T., Torroni, A., Brown, M. D., Shoffner, J. M. <strong>Report of the committee on human mitochondrial DNA.In: Cuticchia, A. J.; Pearson, P. L. (eds.) : Human Gene Mapping, 1993: A Compendium.</strong> Baltimore: Johns Hopkins Univ. Press (pub.) 1994. Pp. 813-845."None>Wallace et al., 1994</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7219534" 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>Several allelic variants have been reported for MTND6, most associated with Leber hereditary optic neuropathy (LHON): MTND6*LHON14484C (<a href="#0001">516006.0001</a>), MTND6*LDYT14459A (<a href="#0002">516006.0002</a>), and MTND6*LDYT14596A (<a href="#0003">516006.0003</a>). <a href="#37" class="mim-tip-reference" title="Ravn, K., Wibrand, F., Hansen, F. J., Horn, N., Rosenberg, T., Schwartz, M. <strong>An mtDNA mutation, 14453G-A, in the NADH dehydrogenase subunit 6 associated with severe MELAS syndrome.</strong> Europ. J. Hum. Genet. 9: 805-809, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11781695/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11781695</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200712" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11781695">Ravn et al. (2001)</a> identified a mutation, MTND6*MELAS14453A (<a href="#0005">516006.0005</a>), associated with MELAS syndrome (<a href="/entry/540000">540000</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11781695" 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>Most mtDNA mutations that cause human disease are mild to moderately deleterious, yet many random mtDNA changes would be expected to be severe. To determine the fate of the more severe mtDNA mutations, <a href="#17" class="mim-tip-reference" title="Fan, W., Waymire, K. G., Narula, N., Li, P., Rocher, C., Coskun, P. E., Vannan, M. A., Narula, J., MacGregor, G. R., Wallace, D. C. <strong>A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations.</strong> Science 319: 958-962, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18276892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18276892</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18276892[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/10.1126/science.1147786" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18276892">Fan et al. (2008)</a> introduced mtDNAs containing 2 mutations that affect oxidative phosphorylation, one mild and one severe, into the female mouse germ line. The severe mutation, 13885insC, created a frameshift mutation in the ND6 gene. When homoplasmic, this mutation inactivates oxidative phosphorylation complex I. The mild mutation was a missense mutation, T6589C, in the cytochrome c oxidase subunit 1 gene (COI; <a href="/entry/516030">516030</a>) that converted the highly conserved valine at codon 421 to alanine (V421A). When homoplasmic, this mutation reduces the activity of oxidative phosphorylation complex IV by 50%. <a href="#17" class="mim-tip-reference" title="Fan, W., Waymire, K. G., Narula, N., Li, P., Rocher, C., Coskun, P. E., Vannan, M. A., Narula, J., MacGregor, G. R., Wallace, D. C. <strong>A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations.</strong> Science 319: 958-962, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18276892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18276892</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18276892[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/10.1126/science.1147786" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18276892">Fan et al. (2008)</a> observed that the severe ND6 mutation was selectively eliminated during oogenesis within 4 generations, whereas the milder COI mutation was retained throughout multiple generations even though the offspring consistently developed mitochondrial myopathy and cardiomyopathy. Thus, <a href="#17" class="mim-tip-reference" title="Fan, W., Waymire, K. G., Narula, N., Li, P., Rocher, C., Coskun, P. E., Vannan, M. A., Narula, J., MacGregor, G. R., Wallace, D. C. <strong>A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations.</strong> Science 319: 958-962, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18276892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18276892</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18276892[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/10.1126/science.1147786" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18276892">Fan et al. (2008)</a> concluded that severe mitochondrial DNA mutations appear to be selectively eliminated from the female germ line, thereby minimizing their impact on population fitness. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18276892" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#35" class="mim-tip-reference" title="Piccoli, C., Ripoli, M., Quarato, G., Scrima, R., D'Aprile, A., Boffoli, D., Margaglione, M., Criscuolo, C., De Michele, G., Sardanelli, A., Papa, S., Capitanio, N. <strong>Coexistence of mutations in PINK1 and mitochondrial DNA in early onset parkinsonism. (Letter)</strong> J. Med. Genet. 45: 596-602, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18524835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18524835</a>] [<a href="https://doi.org/10.1136/jmg.2008.058628" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18524835">Piccoli et al. (2008)</a> presented evidence that mutations in the MTND6 gene (<a href="#0008">516006.0008</a>) may modify the onset and severity of Parkinson disease (see, e.g., PARK6, <a href="/entry/605909">605909</a>) caused by nuclear mutations. See also <a href="/entry/556500">556500</a> for a discussion of Parkinson disease associated with mutations in mitochondrial genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18524835" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an oncocytic tumor (<a href="/entry/553000">553000</a>) of the adnexal lacrimal glands of the conjunctiva, <a href="#5" class="mim-tip-reference" title="Bartoletti-Stella, A., Salfi, N. C. M., Ceccarelli, C., Attimonelli, M., Romeo, G., Gasparre, G. <strong>Mitochondrial DNA mutations in oncocytic adnexal lacrimal glands of the conjunctiva. (Letter)</strong> Arch. Ophthal. 129: 664-666, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21555623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21555623</a>] [<a href="https://doi.org/10.1001/archophthalmol.2011.95" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21555623">Bartoletti-Stella et al. (2011)</a> analyzed the entire mtDNA sequence and identified a frameshift mutation in MTND6 (<a href="#0009">516006.0009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21555623" 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="#22" class="mim-tip-reference" title="Ishikawa, K., Takenaga, K., Akimoto, M., Koshikawa, N., Yamaguchi, A., Imanishi, H., Nakada, K., Honma, Y., Hayashi, J.-I. <strong>ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis.</strong> Science 320: 661-664, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18388260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18388260</a>] [<a href="https://doi.org/10.1126/science.1156906" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18388260">Ishikawa et al. (2008)</a> used cytoplasmic hybrid (cybrid) technology to replace the endogenous mtDNA in a mouse tumor cell line that was poorly metastatic with mtDNA from a cell line that was highly metastatic, and vice versa. Using assays of metastasis in mice, they found that the recipient tumor cells acquired the metastatic potential of the transferred mtDNA. The mtDNA conferring high metastatic potential contained G13997A and 13885insC mutations in the gene encoding NADH dehydrogenase subunit 6 (ND6). These mutations produced a deficiency in respiratory complex I activity and were associated with overproduction of reactive oxygen species. Pretreatment of the highly metastatic tumor cells with reactive oxygen species scavengers suppressed their metastatic potential in mice. <a href="#22" class="mim-tip-reference" title="Ishikawa, K., Takenaga, K., Akimoto, M., Koshikawa, N., Yamaguchi, A., Imanishi, H., Nakada, K., Honma, Y., Hayashi, J.-I. <strong>ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis.</strong> Science 320: 661-664, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18388260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18388260</a>] [<a href="https://doi.org/10.1126/science.1156906" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18388260">Ishikawa et al. (2008)</a> concluded that mtDNA mutations can contribute to tumor progression by enhancing the metastatic potential of tumor cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18388260" 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">rs199476104 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476104;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=rs199476104" 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=rs199476104" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>This allele changes the weakly conserved methionine at amino acid 64 to a valine (M64V). It is found in approximately 15% of Leber optic atrophy (LHON; <a href="/entry/535000">535000</a>) patients, but has not been observed in any controls (less than 0.4%). It generally occurs in association with other LHON mutations. In one large Australian pedigree manifesting LHON and neurological disease, this allele occurred together with MTND1*LHON4160C (<a href="/entry/516000#0002">516000.0002</a>). In most other pedigrees, the MTND6*LHON14484C allele is found together with MTND5*LHON13708A (<a href="/entry/516005#0001">516005.0001</a>) in most LHON pedigrees, MTCYB*LHON15257A (<a href="/entry/516020#0001">516020.0001</a>) or MTND1*LHON3394C (<a href="/entry/516000#0004">516000.0004</a>) in a subset of these, and MTCYB*LHON15812A (<a href="/entry/516005#0001">516005.0001</a>) and in one case MTND2*LHON5244A (<a href="/entry/516001#0002">516001.0002</a>) in a subset of the MTCTB*LHON15257A pedigrees. The MTND6*LHON14484C + MTND1*LHON4160C pedigree is homoplasmic, with 76% of the maternal relatives affected, of which 54% are males. In the other MTND1*LHON 4160C pedigrees, the MTND6*LHON14484C pedigrees have all been homoplasmic except one, and between 27 and 80% of maternal relatives are affected, 68% of these being males. Patients with this mutation have an unusually high predilection for visual recovery (37%) (<a href="#7" class="mim-tip-reference" title="Brown, M. D., Voljavec, A. S., Lott, M. T., MacDonald, I., Wallace, D. C. <strong>Leber's hereditary optic neuropathy; a model for mitochondrial neurodegenerative diseases.</strong> FASEB J. 6: 2791-2799, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1634041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1634041</a>] [<a href="https://doi.org/10.1096/fasebj.6.10.1634041" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1634041">Brown et al., 1992</a>; Johns et al. (<a href="#24" class="mim-tip-reference" title="Johns, D. R., Neufeld, M. J., Park, R. D. <strong>An ND-6 mitochondrial DNA mutation associated with Leber hereditary optic neuropathy.</strong> Biochem. Biophys. Res. Commun. 187: 1551-1557, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1417830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1417830</a>] [<a href="https://doi.org/10.1016/0006-291x(92)90479-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1417830">1992</a>, <a href="#23" class="mim-tip-reference" title="Johns, D. R., Heher, K. L., Miller, N. R., Smith, K. H. <strong>Leber's hereditary optic neuropathy. Clinical manifestations of the 14484 mutation.</strong> Arch. Ophthal. 111: 495-498, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8470982/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8470982</a>] [<a href="https://doi.org/10.1001/archopht.1993.01090040087038" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8470982">1993</a>); <a href="#28" class="mim-tip-reference" title="Mackey, D., Howell, N. <strong>A variant of Leber hereditary optic neuropathy characterized by recovery of vision and by an unusual mitochondrial genetic etiology.</strong> Am. J. Hum. Genet. 51: 1218-1228, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1463007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1463007</a>]" pmid="1463007">Mackey and Howell, 1992</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1634041+8470982+1463007+1417830" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Brown, M. D., Sun, F., Wallace, D. C. <strong>Clustering of Caucasian Leber hereditary optic neuropathy patients containing the 11778 or 14484 mutations on an mtDNA lineage.</strong> Am. J. Hum. Genet. 60: 381-387, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9012411/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9012411</a>]" pmid="9012411">Brown et al. (1997)</a> demonstrated that the 14484C mutation, unlike the other 2 primary LHON mutations (3460 and 11778), is not distributed on the phylogeny in proportion to the frequencies of the major Caucasian mtDNA haplogroups found in North America. The 14484 mutation was shown to occur on the haplogroup J background more frequently than expected, consistent with the observation that approximately 75% of worldwide 14484-positive LHON patients occur in association with haplogroup J. The 11778 mutation (<a href="/entry/516003#0001">516003.0001</a>) also exhibited a moderate clustering on haplogroup J. Their finding suggested a pathogenic role for a subset of LHON secondary mutations and their interaction with primary mutations, and provides support for a polygenic model for LHON expression in some cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9012411" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Carelli, V., Barboni, P., Zacchini, A., Mancini, R., Monari, L., Cevoli, S., Liguori, R., Sensi, M., Lugaresi, E., Montagna, P. <strong>Leber's hereditary optic neuropathy (LHON) with 14484/ND6 mutation in a North African patient.</strong> J. Neurol. Sci. 160: 183-188, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9849804/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9849804</a>] [<a href="https://doi.org/10.1016/s0022-510x(98)00239-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9849804">Carelli et al. (1998)</a> described LHON in a patient of North African origin carrying the 14484 mutation of the ND6 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9849804" 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="#29" class="mim-tip-reference" title="Macmillan, C., Johns, T. A., Fu, K., Shoubridge, E. A. <strong>Predominance of the T14484C mutation in French-Canadian families with Leber hereditary optic neuropathy is due to a founder effect. (Letter)</strong> Am. J. Hum. Genet. 66: 332-335, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10631164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10631164</a>] [<a href="https://doi.org/10.1086/302716" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10631164">Macmillan et al. (2000)</a> analyzed 27 independently referred French-Canadian families with LHON and the 14484T-C mutation, all of which were homoplasmic for the 14484T-C mutation. They found 8 homoplasmic transition mutations (16069C-T, 16126T-C, 16213G-A, 73A-G, 185G-A, 228G-A, 263A-G, and 295C-T), compared with the Cambridge sequence of the Sanger group (<a href="#1" class="mim-tip-reference" title="Anderson, S., Bankier, A. T., Barrell, B. G., de Bruijn, M. H. L., Coulson, A. R., Drouin, J., Eperon, I. C., Nierlich, D. P., Roe, B. A., Sanger, F., Schreier, P. H., Smith, A. J. H., Staden, R., Young, I. G. <strong>Sequence and organization of the human mitochondrial genome.</strong> Nature 290: 457-465, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7219534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7219534</a>] [<a href="https://doi.org/10.1038/290457a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7219534">Anderson et al., 1981</a>), in the families with the 14484T-C mutation. Of the 27 families analyzed, 26 shared identical substitutions at all 8 sites that were different from the Cambridge sequence. Six of these mutations were found only in families with the 14484T-C mutation and not in either the family with 11778G-A or the family without LHON. The data were interpreted as demonstrating that French-Canadian families with LHON and the 14484T-C mutation probably share the same maternal lineage and suggested that they may all have been derived from a single founder woman. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10631164+7219534" 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>The first report of LHON in French Canadians dated from 1970, when a large pedigree from southwestern Quebec was described by <a href="#8" class="mim-tip-reference" title="Brunette, J.-R., Bernier, R.-G. <strong>Diagnostic et pronostic de la maladie de Leber: incidence de la recuperation totale spontanee.</strong> Un. Med. Canada 99: 643-652, 1970.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5511487/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5511487</a>]" pmid="5511487">Brunette and Bernier (1970)</a>. A high rate (19.5%) of spontaneous recovery was observed in this large kindred: 4 patients regained a visual acuity of 20/50 or better in at least 1 eye and 6 regained bilateral normal vision. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5511487" 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="#31" class="mim-tip-reference" title="Nishioka, T., Tasaki, M., Soemantri, A., Dyat, M., Susanto, J. C., Tamam, M., Sudarmanto, B., Ishida, T. <strong>Leber's hereditary optic neuropathy with 14484 mutation in Central Java, Indonesia.</strong> J. Hum. Genet. 48: 385-389, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12827453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12827453</a>] [<a href="https://doi.org/10.1007/s10038-003-0042-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12827453">Nishioka et al. (2003)</a> identified the 14484T-C mutation in a 6-generation Indonesian LHON family. All of the maternal lineages had the 14484T-C mutation in homoplasmic form. Penetrance of the disease (33.3%) and male predominance (3:1) was similar to other worldwide LHON with the 14484T-C mutation. The incidence of offspring born to affected mothers was no different from that of unaffected mothers, and the age distribution of cases was no higher than that of asymptomatic carriers. Eight secondary mutations were sought but not detected. Patients of this family belonged to haplogroup M. These findings supported the idea that the mtDNA backgrounds involved in the expression of LHON mutations in southeast Asians are different from those of Europeans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12827453" 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 platelet submitochondrial particles from 9 individuals with the 14484T-C mutation, <a href="#10" class="mim-tip-reference" title="Carelli, V., Ghelli, A., Bucchi, L., Montagna, P., De Negri, A., Leuzzi, V., Carducci, C., Lenaz, G., Lugaresi, E., Degli Esposti, M. <strong>Biochemical features of mtDNA 14484 (ND6/M64V) point mutation associated with Leber's hereditary optic neuropathy.</strong> Ann. Neurol. 45: 320-328, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10072046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10072046</a>]" pmid="10072046">Carelli et al. (1999)</a> found no difference in overall complex I activity compared to controls. However, in the particles with the mutation, they detected significantly increased sensitivity to 2 inhibitors at the ubiquinol product site, myxothiazol and nonylbenzoquinol. The mutation affects the highly conserved helix C, the interaction site of ubiquinol products. <a href="#10" class="mim-tip-reference" title="Carelli, V., Ghelli, A., Bucchi, L., Montagna, P., De Negri, A., Leuzzi, V., Carducci, C., Lenaz, G., Lugaresi, E., Degli Esposti, M. <strong>Biochemical features of mtDNA 14484 (ND6/M64V) point mutation associated with Leber's hereditary optic neuropathy.</strong> Ann. Neurol. 45: 320-328, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10072046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10072046</a>]" pmid="10072046">Carelli et al. (1999)</a> noted that the biochemical defect caused by the 14484T-C change resembles that reported for the ND4 11778 mutation (<a href="/entry/516003#0001">516003.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10072046" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Howell, N., Oostra, R.-J., Bolhuis, P. A., Spruijt, L., Clarke, L. A., Mackey, D. A., Preston, G., Herrnstadt, C. <strong>Sequence analysis of the mitochondrial genomes from Dutch pedigrees with Leber hereditary optic neuropathy.</strong> Am. J. Hum. Genet. 72: 1460-1469, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12736867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12736867</a>] [<a href="https://doi.org/10.1086/375537" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12736867">Howell et al. (2003)</a> determined the complete mtDNA sequences of 63 Dutch pedigrees with LHON, 56 of which carried 1 of the classic LHON mutations at nucleotide 3460 (<a href="/entry/516000#0001">516000.0001</a>), 11778 (<a href="/entry/516003#0001">516003.0001</a>), or 14484. The most striking incidence in which the mtDNA was either identical or related by descent was a haplogroup J mtDNA that carried the 14484 LHON mutation. In 7 of the pedigrees, 4 different but related mitochondrial genotypes were identified. The control region of the founder sequence for these Dutch pedigrees with LHON matched the control region sequence that <a href="#29" class="mim-tip-reference" title="Macmillan, C., Johns, T. A., Fu, K., Shoubridge, E. A. <strong>Predominance of the T14484C mutation in French-Canadian families with Leber hereditary optic neuropathy is due to a founder effect. (Letter)</strong> Am. J. Hum. Genet. 66: 332-335, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10631164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10631164</a>] [<a href="https://doi.org/10.1086/302716" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10631164">Macmillan et al. (2000)</a> identified in the founder mtDNA of French-Canadian pedigrees with LHON. In addition, <a href="#21" class="mim-tip-reference" title="Howell, N., Oostra, R.-J., Bolhuis, P. A., Spruijt, L., Clarke, L. A., Mackey, D. A., Preston, G., Herrnstadt, C. <strong>Sequence analysis of the mitochondrial genomes from Dutch pedigrees with Leber hereditary optic neuropathy.</strong> Am. J. Hum. Genet. 72: 1460-1469, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12736867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12736867</a>] [<a href="https://doi.org/10.1086/375537" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12736867">Howell et al. (2003)</a> obtained a perfect match between the Dutch 14484 founder sequence and the complete mtDNA sequences of 2 Canadian pedigrees with LHON. These results indicated that these Dutch and French-Canadian 14484 pedigrees with LHON shared a common ancestor, that the single origin of the 14484 mutation in this 'megalineage' occurred before the year 1600, and that there is a 14484/haplogroup J founder effect. <a href="#21" class="mim-tip-reference" title="Howell, N., Oostra, R.-J., Bolhuis, P. A., Spruijt, L., Clarke, L. A., Mackey, D. A., Preston, G., Herrnstadt, C. <strong>Sequence analysis of the mitochondrial genomes from Dutch pedigrees with Leber hereditary optic neuropathy.</strong> Am. J. Hum. Genet. 72: 1460-1469, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12736867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12736867</a>] [<a href="https://doi.org/10.1086/375537" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12736867">Howell et al. (2003)</a> estimated that this lineage (including the 14484 LHON mutation) arose 900 to 1,800 years ago. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10631164+12736867" 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 genealogic reconstructions of maternal lineages, <a href="#27" class="mim-tip-reference" title="Laberge, A.-M., Jomphe, M., Houde, L., Vezina, H., Tremblay, M., Desjardins, B., Labuda, D., St-Hilaire, M., Macmillan, C., Shoubridge, E. A., Brais, B. <strong>A 'fille du roy' introduced the T14484C Leber hereditary optic neuropathy mutation in French Canadians.</strong> Am. J. Hum. Genet. 77: 313-317, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15954041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15954041</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15954041[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/432491" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15954041">Laberge et al. (2005)</a> identified a woman married in Quebec City in 1669 as the shared female ancestor for 11 of 13 French Canadian individuals with the T14484C mutation who were not previously known to be related. The individuals carried identical mitochondrial haplogroups. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15954041" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Elliott, H. R., Samuels, D. C., Eden, J. A., Relton, C. L., Chinnery, P. F. <strong>Pathogenic mitochondrial DNA mutations are common in the general population.</strong> Am. J. Hum. Genet. 83: 254-260, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18674747/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18674747</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.07.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18674747">Elliott et al. (2008)</a> determined the frequency of 10 mitochondrial point mutations in 3,168 neonatal cord blood samples from sequential live births in North Cumbria in England, analyzing matched maternal blood samples to estimate the de novo mutation rate. Mitochondrial DNA mutations were detected in 15 offspring (0.54%, 95% confidence interval = 0.30-0.89%). Of these live births, 0.00107% (95% confidence interval = 0.00087-0.0127) harbored a mutation not detected in the mother's blood, providing an estimate of the de novo mutation rate. The mitochondrial 14484T-C mutation was only found on subbranches of mtDNA haplogroup J. <a href="#16" class="mim-tip-reference" title="Elliott, H. R., Samuels, D. C., Eden, J. A., Relton, C. L., Chinnery, P. F. <strong>Pathogenic mitochondrial DNA mutations are common in the general population.</strong> Am. J. Hum. Genet. 83: 254-260, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18674747/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18674747</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.07.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18674747">Elliott et al. (2008)</a> concluded that at least 1 in 200 healthy humans harbors a pathogenic mitochondrial DNA mutation that potentially causes disease in the offspring of female carriers. The exclusive detection of mitochondrial 1448T-C on haplogroup J implicates the background mitochondrial DNA haplotype in mutagenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18674747" 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 LEBER OPTIC ATROPHY AND DYSTONIA</strong>
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LEBER OPTIC ATROPHY, INCLUDED<br />
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LEIGH SYNDROME DUE TO MITOCHONDRIAL COMPLEX I DEFICIENCY, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199476105 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476105;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=rs199476105" 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=rs199476105" 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=RCV000010326 OR RCV000010327 OR RCV000010328 OR RCV000144019 OR RCV001796715 OR RCV004696634" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010326, RCV000010327, RCV000010328, RCV000144019, RCV001796715, RCV004696634" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010326...</a>
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<p>In affected members of a large Hispanic family with Leber optic atrophy and dystonia (<a href="/entry/500001">500001</a>), <a href="#25" class="mim-tip-reference" title="Jun, A. S., Brown, M. D., Wallace, D. C. <strong>A mitochondrial DNA mutation at nucleotide pair 14459 of the NADH dehydrogenase subunit 6 gene associated with maternally inherited Leber hereditary optic neuropathy and dystonia.</strong> Proc. Nat. Acad. Sci. 91: 6206-6210, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8016139/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8016139</a>] [<a href="https://doi.org/10.1073/pnas.91.13.6206" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8016139">Jun et al. (1994)</a> identified a heteroplasmic 14459G-A transition in the MTND6 gene. This mutation results in an ala72-to-val (A72V) substitution. Leber optic atrophy predominated in the early generations and dystonia together with bilateral striatal necrosis was found in later generations. Among members of the later generations, 48% of the maternal relatives manifested dystonia, 10% LHON, and 3% LHON and dystonia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8016139" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#38" class="mim-tip-reference" title="Shoffner, J. M., Brown, M. D., Stugard, C., Jun, A. S., Pollock, S., Haas, R. H., Kaufman, A., Koontz, D., Kim, Y., Graham, J. R., Smith, E., Dixon, J., Wallace, D. C. <strong>Leber's hereditary optic neuropathy plus dystonia is caused by a mitochondrial DNA point mutation.</strong> Ann. Neurol. 38: 163-169, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7654063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7654063</a>] [<a href="https://doi.org/10.1002/ana.410380207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7654063">Shoffner et al. (1995)</a> identified a heteroplasmic 14459G-A mutation in a mother and daughter with isolated LHON (<a href="/entry/535000">535000</a>) and in an unrelated girl with childhood-onset generalized dystonia. The daughter in the first family showed unilateral lesions in the basal ganglia on MRI, whereas the child in the second family had extensive bilateral lesions in the basal ganglia. Although the child with dystonia was severely affected, with dysarthria, quadriparesis, scoliosis, and pes cavus, intelligence was normal. The mother in the first family showed 50% heteroplasmy for the mutation in leukocytes, whereas her daughter showed homoplasmy in leukocytes and muscle. The girl in the second family showed 50% heteroplasmy for the mutation in skeletal muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7654063" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 patients with Leigh syndrome (<a href="/entry/500017">500017</a>) from 2 unrelated families, <a href="#26" class="mim-tip-reference" title="Kirby, D. M., Kahler, S. G., Freckmann, M.-L., Reddihough, D., Thorburn, D. R. <strong>Leigh disease caused by the mitochondrial DNA G14459A mutation in unrelated families.</strong> Ann. Neurol. 48: 102-104, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10894222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10894222</a>]" pmid="10894222">Kirby et al. (2000)</a> identified the 14459G-A mutation in the MTND6 gene. There was no evidence of Leber optic atrophy or dystonia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10894222" 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="#20" class="mim-tip-reference" title="Gropman, A., Chen, T.-J., Perng, C.-L., Krasnewich, D., Chernoff, E., Tifft, C., Wong, L.-J. C. <strong>Variable clinical manifestation of homoplasmic G14459A mitochondrial DNA mutation.</strong> Am. J. Med. Genet. 124A: 377-382, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14735585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14735585</a>] [<a href="https://doi.org/10.1002/ajmg.a.20456" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14735585">Gropman et al. (2004)</a> reported a family with a homoplasmic 14459G-A mtDNA mutation and a broad spectrum of clinical manifestations due to complex I deficiency (<a href="/entry/252010">252010</a>). The proband had anarthria, dystonia, spasticity, and mild encephalopathy, and an MRI revealed bilateral, symmetric basal ganglia lucencies associated with cerebral and systemic lactic acidosis. Among other family members with the mutation, some were asymptomatic and others were symptomatic with variable clinical and laboratory features, confirming the heterogeneous phenotype of homoplasmic 14459G-A mtDNA mutations, even within the same family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14735585" 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="#47" class="mim-tip-reference" title="Watanabe, M., Mita, S., Takita, T., Goto, Y., Uchino, M., Imamura, S. <strong>Leber's hereditary optic neuropathy with dystonia in Japanese family.</strong> J. Neurol. Sci. 243: 31-34, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16380132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16380132</a>] [<a href="https://doi.org/10.1016/j.jns.2005.11.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16380132">Watanabe et al. (2006)</a> identified the 14459G-A mutation in 2 Japanese sisters with childhood-onset dystonia, mental deterioration, adult-onset LHON, and basal ganglia lesions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16380132" 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 LEBER OPTIC ATROPHY AND DYSTONIA</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">rs387906424 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906424;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=rs387906424" 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=rs387906424" 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=RCV000010329 OR RCV000055704 OR RCV004791208" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010329, RCV000055704, RCV004791208" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010329...</a>
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<p>In a large Dutch kindred in which Leber optic atrophy was associated with hereditary spastic dystonia (see <a href="/entry/500001">500001</a> and <a href="/entry/535000">535000</a>) in some members whereas only 1 type of abnormality was found in others, <a href="#15" class="mim-tip-reference" title="De Vries, D. D., Went, L. N., Bruyn, G. W., Scholte, H. R., Hofstra, R. M. W., Bolhuis, P. A., van Oost, B. A. <strong>Genetic and biochemical impairment of mitochondrial complex I activity in a family with Leber hereditary optic neuropathy and hereditary spastic dystonia.</strong> Am. J. Hum. Genet. 58: 703-711, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8644732/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8644732</a>]" pmid="8644732">De Vries et al. (1996)</a> found 2 previously unreported mtDNA mutations. One was a heteroplasmic A-to-G transition at nucleotide position 11696 in the ND4 gene (<a href="/entry/516003#0003">516003.0003</a>) that resulted in the substitution of an isoleucine for valine at amino acid position 312. A second mutation, a homoplasmic T-to-A transition at nucleotide position 14596 in the ND6 gene, resulted in the substitution of a methionine for isoleucine at amino acid residue 26. Biochemical analysis of a muscle biopsy showed severe complex I deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8644732" 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 LEBER OPTIC ATROPHY</strong>
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MTND6, LHON14495G
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199476106 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476106;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=rs199476106" 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=rs199476106" 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=RCV000010330 OR RCV002260588" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010330, RCV002260588" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010330...</a>
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<p><a href="#12" class="mim-tip-reference" title="Chinnery, P. F., Brown, D. T., Andrews, R. M., Singh-Kler, R., Riordan-Eva, P., Lindley, J., Applegarth, D. A., Turnbull, D. M., Howell, N. <strong>The mitochondrial ND6 gene is a hot spot for mutations that cause Leber's hereditary optic neuropathy.</strong> Brain 124: 209-218, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11133798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11133798</a>] [<a href="https://doi.org/10.1093/brain/124.1.209" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11133798">Chinnery et al. (2001)</a> described 2 pedigrees with Leber optic atrophy (<a href="/entry/535000">535000</a>) that harbored the same novel point mutation in the MTND6 gene, i.e., a 14495A-G change resulting in a leu-to-ser substitution. The mutation was heteroplasmic in both families, and sequencing of the mitochondrial genome confirmed that the mutation arose on 2 independent occasions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11133798" 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 MELAS SYNDROME</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">rs199476107 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476107;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=rs199476107" 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=rs199476107" 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=RCV000010331 OR RCV000855109 OR RCV002260589" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010331, RCV000855109, RCV002260589" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010331...</a>
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<p>In a sporadic case of MELAS syndrome (<a href="/entry/540000">540000</a>), <a href="#37" class="mim-tip-reference" title="Ravn, K., Wibrand, F., Hansen, F. J., Horn, N., Rosenberg, T., Schwartz, M. <strong>An mtDNA mutation, 14453G-A, in the NADH dehydrogenase subunit 6 associated with severe MELAS syndrome.</strong> Europ. J. Hum. Genet. 9: 805-809, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11781695/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11781695</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200712" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11781695">Ravn et al. (2001)</a> identified a heteroplasmic G-to-A transition at nucleotide 14453 of the ND6 gene, resulting in an ala74-to-val (A74V) substitution. The patient was a 7-year-old girl with normal development until the age of 2 years. Between 2 and 3 years of age, she had episodes of vomiting followed by ketotic acidosis. She developed myoclonic epilepsy, general weakness, and ataxia with intermitting dystonia. Magnetic resonance scans showed cerebellar hypoplasia and multiple infarctions in both hemispheres. A muscle biopsy revealed lipid storage myopathy with normal mitochondria on electron microscopy. The patient developed episodes of lethargy, lactic acidosis, and alternating uniparesis. Ophthalmologic examination revealed no sign of atrophy of the optic nerve but abolished visual evoked potentials (VEP). The mother was healthy, with no history of a mitochondrial disorder. Mitochondrial enzyme analysis in the patient showed a decreased activity of complex I in muscle. Sequencing of the entire mtDNA, except part of the D loop, revealed heteroplasmy for the 14453G-A mutation in 82% of the mtDNA of the patient's muscle and 78% in blood. The mutation was not detected in the blood of the mother nor in 50 healthy controls. In addition to the 14453G-A mutation, <a href="#37" class="mim-tip-reference" title="Ravn, K., Wibrand, F., Hansen, F. J., Horn, N., Rosenberg, T., Schwartz, M. <strong>An mtDNA mutation, 14453G-A, in the NADH dehydrogenase subunit 6 associated with severe MELAS syndrome.</strong> Europ. J. Hum. Genet. 9: 805-809, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11781695/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11781695</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200712" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11781695">Ravn et al. (2001)</a> identified 2 other homoplasmic mutations in the mtDNA of their patient, 5628T-C in the MTTA gene (<a href="/entry/590000">590000</a>) and 13535A-G in the MTND5 gene (<a href="/entry/516005">516005</a>), which might have contributed to the observed decrease in activity of complex I and the severe phenotype of the patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11781695" 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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<strong>.0006 LEBER OPTIC ATROPHY</strong>
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MTND6, LHON14482A
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199476108 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476108;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=rs199476108" 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=rs199476108" 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=RCV000010332 OR RCV002260590" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010332, RCV002260590" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010332...</a>
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<p>In 2 maternally related males with Leber optic atrophy (<a href="/entry/535000">535000</a>) characterized by visual recovery, <a href="#43" class="mim-tip-reference" title="Valentino, M. L., Avoni, P., Barboni, P., Pallotti, F., Rengo, C., Torroni, A., Bellan, M., Baruzzi, A., Carelli, V. <strong>Mitochondrial DNA nucleotide changes C14482G and C14482A in the ND6 gene are pathogenic for Leber's hereditary optic neuropathy.</strong> Ann. Neurol. 51: 774-778, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12112086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12112086</a>] [<a href="https://doi.org/10.1002/ana.10193" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12112086">Valentino et al. (2002)</a> identified a homoplasmic 14482C-A transversion in the MTND6 gene, resulting in a met64-to-ile change in an area known to be a mutation hotspot. Sequencing of the area showed that the mutation was found on a haplogroup J mtDNA background, similar to the 14484T-C mutation (<a href="#0001">516006.0001</a>), which results in a met64-to-val substitution. Methionine, isoleucine, and valine are all hydrophobic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12112086" 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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<strong>.0007 LEIGH SYNDROME DUE TO MITOCHONDRIAL COMPLEX I DEFICIENCY</strong>
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STRIATAL NECROSIS, BILATERAL, WITH DYSTONIA, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199476109 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476109;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=rs199476109" 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=rs199476109" 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=RCV000010333 OR RCV000010334 OR RCV000144020 OR RCV002247307 OR RCV003162239" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010333, RCV000010334, RCV000144020, RCV002247307, RCV003162239" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010333...</a>
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<p>In a male infant with Leigh syndrome (<a href="/entry/500017">500017</a>), <a href="#42" class="mim-tip-reference" title="Ugalde, C., Triepels, R. H., Coenen, M. J. H., van den Heuvel, L. P., Smeets, R., Uusimaa, J., Briones, P., Campistol, J., Majamaa, K., Smeitink, J. A. M., Nijtmans, L. G. J. <strong>Impaired complex I assembly in a Leigh syndrome patient with a novel missense mutation in the ND6 gene.</strong> Ann. Neurol. 54: 665-669, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14595656/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14595656</a>] [<a href="https://doi.org/10.1002/ana.10734" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14595656">Ugalde et al. (2003)</a> identified a heteroplasmic 14487T-C transition in the MTND6 gene, resulting in a met63-to-val (M63V) substitution. The patient presented at 4 months of age with tonic-clonic seizures, and was later found to have motor retardation, hypotonia, deafness, pyramidal and extrapyramidal tract signs, and episodic brainstem events with oculomotor palsies, strabismus, and recurrent apnea. Laboratory studies showed lactic acidemia and basal ganglia lesions. He died at age 7 months. The patient's mother had 24% mutant load in blood, and the patient had 65% mutant load in muscle and liver, and 86% mutant load in fibroblasts. Further studies showed that the mutation occurred in the most conserved transmembrane helix of the protein and caused an impaired assembly of complex I (<a href="/entry/252010">252010</a>). <a href="#42" class="mim-tip-reference" title="Ugalde, C., Triepels, R. H., Coenen, M. J. H., van den Heuvel, L. P., Smeets, R., Uusimaa, J., Briones, P., Campistol, J., Majamaa, K., Smeitink, J. A. M., Nijtmans, L. G. J. <strong>Impaired complex I assembly in a Leigh syndrome patient with a novel missense mutation in the ND6 gene.</strong> Ann. Neurol. 54: 665-669, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14595656/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14595656</a>] [<a href="https://doi.org/10.1002/ana.10734" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14595656">Ugalde et al. (2003)</a> commented on the severe phenotypic expression of the M63V mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14595656" 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 unrelated males with progressive generalized dystonia and bilateral striatal necrosis beginning at ages 4 and 6 years, respectively, <a href="#40" class="mim-tip-reference" title="Solano, A., Roig, M., Vives-Bauza, C., Hernandez-Pena, J., Garcia-Arumi, E., Playan, A., Lopez-Perez, M. J., Andreu, A. L., Montoya, J. <strong>Bilateral striatal necrosis associated with a novel mutation in the mitochondrial ND6 gene.</strong> Ann. Neurol. 54: 527-530, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14520668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14520668</a>] [<a href="https://doi.org/10.1002/ana.10682" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14520668">Solano et al. (2003)</a> identified the M63V mutation. In 1 patient, there was a high proportion of mutant mtDNA in muscle (93%) and in blood (67%). His unaffected mother showed 26% heteroplasmy in blood. Biochemical analysis showed isolated complex I deficiency. <a href="#40" class="mim-tip-reference" title="Solano, A., Roig, M., Vives-Bauza, C., Hernandez-Pena, J., Garcia-Arumi, E., Playan, A., Lopez-Perez, M. J., Andreu, A. L., Montoya, J. <strong>Bilateral striatal necrosis associated with a novel mutation in the mitochondrial ND6 gene.</strong> Ann. Neurol. 54: 527-530, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14520668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14520668</a>] [<a href="https://doi.org/10.1002/ana.10682" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14520668">Solano et al. (2003)</a> noted that other reports (e.g., <a href="#18" class="mim-tip-reference" title="Funalot, B., Reynier, P., Vighetto, A., Ranoux, D., Bonnefont, J.-P., Godinot, C. <strong>Malthiery, Y.; Mas, J.-L.: Leigh-like encephalopathy complicating Leber's hereditary optic neuropathy.</strong> Ann. Neurol. 52: 374-377, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12205655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12205655</a>] [<a href="https://doi.org/10.1002/ana.10299" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12205655">Funalot et al., 2002</a>) had found association between mutation in MTND6 and dystonia and bilateral striatal necrosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14520668+12205655" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 PARKINSON DISEASE 6, MODIFIER OF</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">rs199476110 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476110;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=rs199476110" 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=rs199476110" 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=RCV000010335 OR RCV000855091" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010335, RCV000855091" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010335...</a>
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<p>In a patient with early-onset Parkinson disease (PARK6; <a href="/entry/605909">605909</a>) due to a homozygous mutation in the PINK1 gene (<a href="/entry/608309#0002">608309.0002</a>), <a href="#35" class="mim-tip-reference" title="Piccoli, C., Ripoli, M., Quarato, G., Scrima, R., D'Aprile, A., Boffoli, D., Margaglione, M., Criscuolo, C., De Michele, G., Sardanelli, A., Papa, S., Capitanio, N. <strong>Coexistence of mutations in PINK1 and mitochondrial DNA in early onset parkinsonism. (Letter)</strong> J. Med. Genet. 45: 596-602, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18524835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18524835</a>] [<a href="https://doi.org/10.1136/jmg.2008.058628" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18524835">Piccoli et al. (2008)</a> identified a homoplasmic 14319T-C mutation in the MTND6 gene and a homoplasmic mutation in the MTND6 gene (<a href="#0010">516006.0010</a>). The 14319T-C mutation results in an asn119-to-asp (N119D) substitution in the fifth of 6 predicted transmembrane helices. The patient had onset at age 22 years. His mother, who was heterozygous for the PINK1 mutation, was also homoplasmic for both mitochondrial mutations and showed disease onset at age 53. The father was heterozygous for the PINK1 mutation only and unaffected at age 79. Biochemical studies of the proband's fibroblasts showed mitochondrial dysfunction, with decreased amounts of cytochrome c oxidase, impaired complex I activity, and increased hydrogen peroxide generation. <a href="#35" class="mim-tip-reference" title="Piccoli, C., Ripoli, M., Quarato, G., Scrima, R., D'Aprile, A., Boffoli, D., Margaglione, M., Criscuolo, C., De Michele, G., Sardanelli, A., Papa, S., Capitanio, N. <strong>Coexistence of mutations in PINK1 and mitochondrial DNA in early onset parkinsonism. (Letter)</strong> J. Med. Genet. 45: 596-602, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18524835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18524835</a>] [<a href="https://doi.org/10.1136/jmg.2008.058628" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18524835">Piccoli et al. (2008)</a> concluded that the presence of the mitochondrial mutations in combination with the PINK1 mutation may have accelerated the onset of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18524835" 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">rs869312882 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869312882;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=rs869312882" 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=rs869312882" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In an oncocytic tumor (<a href="/entry/553000">553000</a>) of the adnexal lacrimal glands of the conjunctiva, <a href="#5" class="mim-tip-reference" title="Bartoletti-Stella, A., Salfi, N. C. M., Ceccarelli, C., Attimonelli, M., Romeo, G., Gasparre, G. <strong>Mitochondrial DNA mutations in oncocytic adnexal lacrimal glands of the conjunctiva. (Letter)</strong> Arch. Ophthal. 129: 664-666, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21555623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21555623</a>] [<a href="https://doi.org/10.1001/archophthalmol.2011.95" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21555623">Bartoletti-Stella et al. (2011)</a> identified a 1-bp insertion (14249insC) in the MTND6 gene, predicted to cause a frameshift and hamper assembly of complex I. The mutation appeared to be heteroplasmic in the tumor, which was confirmed by immunohistochemical analysis showing that MTND6 expression was much fainter in the oncocytic neoplasm compared to nonneoplastic tissue. Ki67 staining revealed a low proliferation index of 1.8%, consistent with the benign nature of the case. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21555623" 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="#Ragan1987" class="mim-tip-reference" title="Ragan, C. I. <strong>Structure of NADH-ubiquinone reductase (complex I).</strong> Curr. Top. Bioenerg. 15: 1-36, 1987.">Ragan (1987)</a>
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<strong>REFERENCES</strong>
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<a id="Anderson1981" class="mim-anchor"></a>
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Anderson, S., Bankier, A. T., Barrell, B. G., de Bruijn, M. H. L., Coulson, A. R., Drouin, J., Eperon, I. C., Nierlich, D. P., Roe, B. A., Sanger, F., Schreier, P. H., Smith, A. J. H., Staden, R., Young, I. G.
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<strong>Sequence and organization of the human mitochondrial genome.</strong>
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Nature 290: 457-465, 1981.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7219534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7219534</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7219534" 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/10.1038/290457a0" target="_blank">Full Text</a>]
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Arizmendi, J. M., Skehel, J. M., Runswick, M. J., Fearnley, I. M., Walker, J. E.
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<strong>Complementary DNA sequences of two 14.5 kDa subunits of NADH:ubiquinone oxidoreductase from bovine heart mitochondria. Complementation of the primary structure of the complex.</strong>
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FEBS Lett. 313: 80-84, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1426273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1426273</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1426273" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0014-5793(92)81189-s" target="_blank">Full Text</a>]
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Attardi, G., Chomyn, A., Doolittle, R. F., Mariottini, P., Ragan, C. I.
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<strong>Seven unidentified reading frames of human mitochondrial DNA encode subunits of the respiratory chain NADH dehydrogenase.</strong>
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Cold Spring Harbor Symp. Quant. Biol. 51: 103-114, 1986.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3472707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3472707</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3472707" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Attardi, G., Chomyn, A., Montoya, J., Ojala, D.
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<strong>Identification and mapping of human mitochondrial genes.</strong>
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Cytogenet. Cell Genet. 32: 85-98, 1982.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7140372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7140372</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7140372" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1159/000131689" target="_blank">Full Text</a>]
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Bartoletti-Stella, A., Salfi, N. C. M., Ceccarelli, C., Attimonelli, M., Romeo, G., Gasparre, G.
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<strong>Mitochondrial DNA mutations in oncocytic adnexal lacrimal glands of the conjunctiva. (Letter)</strong>
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Arch. Ophthal. 129: 664-666, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21555623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21555623</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21555623" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1001/archophthalmol.2011.95" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.91.13.6206" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20075246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20075246</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20075246" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1180674" target="_blank">Full Text</a>]
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<a id="Ugalde2003" class="mim-anchor"></a>
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Ugalde, C., Triepels, R. H., Coenen, M. J. H., van den Heuvel, L. P., Smeets, R., Uusimaa, J., Briones, P., Campistol, J., Majamaa, K., Smeitink, J. A. M., Nijtmans, L. G. J.
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<strong>Impaired complex I assembly in a Leigh syndrome patient with a novel missense mutation in the ND6 gene.</strong>
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Ann. Neurol. 54: 665-669, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14595656/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14595656</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14595656" 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.10734" target="_blank">Full Text</a>]
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<a id="Valentino2002" class="mim-anchor"></a>
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Valentino, M. L., Avoni, P., Barboni, P., Pallotti, F., Rengo, C., Torroni, A., Bellan, M., Baruzzi, A., Carelli, V.
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<strong>Mitochondrial DNA nucleotide changes C14482G and C14482A in the ND6 gene are pathogenic for Leber's hereditary optic neuropathy.</strong>
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Ann. Neurol. 51: 774-778, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12112086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12112086</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12112086" 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.10193" target="_blank">Full Text</a>]
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<a id="Walker1992" class="mim-anchor"></a>
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Walker, J. E., Arizmendi, J. M., Dupuis, A., Fearnley, I. M., Finel, M., Medd, S. M., Pilkington, S. J., Runswick, M. J., Skehel, J. M.
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<strong>Sequences of 20 subunits of NADH:ubiquinone oxidoreductase from bovine heart mitochondria: application of a novel strategy for sequencing proteins using the polymerase chain reaction.</strong>
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J. Molec. Biol. 226: 1051-1072, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1518044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1518044</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1518044" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0022-2836(92)91052-q" target="_blank">Full Text</a>]
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<a id="Wallace1994" class="mim-anchor"></a>
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Wallace, D. C., Lott, M. T., Torroni, A., Brown, M. D., Shoffner, J. M.
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<strong>Report of the committee on human mitochondrial DNA.In: Cuticchia, A. J.; Pearson, P. L. (eds.) : Human Gene Mapping, 1993: A Compendium.</strong>
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Baltimore: Johns Hopkins Univ. Press (pub.) 1994. Pp. 813-845.
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Wallace, D. C., Yang, J., Ye, J., Lott, M. T., Oliver, N. A., McCarthy, J.
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<strong>Computer prediction of peptide maps: Assignment of polypeptides to human and mouse mitochondrial DNA genes by analysis of two-dimensional-proteolytic digest gels.</strong>
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Am. J. Hum. Genet. 38: 461, 1986.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3518425/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3518425</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3518425" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Watanabe2006" class="mim-anchor"></a>
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Watanabe, M., Mita, S., Takita, T., Goto, Y., Uchino, M., Imamura, S.
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<strong>Leber's hereditary optic neuropathy with dystonia in Japanese family.</strong>
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J. Neurol. Sci. 243: 31-34, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16380132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16380132</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16380132" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.jns.2005.11.003" 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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Marla J. F. O'Neill - updated : 9/15/2011
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<div class="row collapse" id="mimCollapseContributors">
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Ada Hamosh - updated : 2/1/2010<br>Cassandra L. Kniffin - updated : 10/6/2008<br>Ada Hamosh - updated : 9/8/2008<br>Ada Hamosh - updated : 6/17/2008<br>Cassandra L. Kniffin - updated : 4/4/2008<br>Ada Hamosh - updated : 3/18/2008<br>Marla J. F. O'Neill - updated : 9/22/2005<br>Victor A. McKusick - updated : 4/28/2005<br>Marla J. F. O'Neill - updated : 6/8/2004<br>Cassandra L. Kniffin - updated : 1/7/2004<br>Cassandra L. Kniffin - updated : 12/23/2003<br>Victor A. McKusick - updated : 10/21/2003<br>Cassandra L. Kniffin - updated : 9/18/2003<br>Victor A. McKusick - updated : 8/27/2003<br>Michael B. Petersen - updated : 7/8/2002<br>Jane Kelly - updated : 7/16/2001<br>Victor A. McKusick - updated : 2/4/2000<br>Victor A. McKusick - updated : 7/19/1999<br>Victor A. McKusick - updated : 4/8/1997<br>Douglas C. Wallace - updated : 4/8/1994
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Creation Date:
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Victor A. McKusick : 3/2/1993
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carol : 05/20/2024
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carol : 05/16/2024<br>carol : 07/08/2016<br>carol : 6/23/2016<br>terry : 9/15/2011<br>terry : 5/24/2011<br>terry : 11/3/2010<br>carol : 11/1/2010<br>terry : 5/26/2010<br>alopez : 2/2/2010<br>terry : 2/1/2010<br>carol : 1/19/2010<br>alopez : 7/15/2009<br>wwang : 10/7/2008<br>ckniffin : 10/6/2008<br>alopez : 9/17/2008<br>terry : 9/8/2008<br>terry : 8/26/2008<br>alopez : 6/19/2008<br>terry : 6/17/2008<br>wwang : 4/15/2008<br>ckniffin : 4/4/2008<br>alopez : 3/26/2008<br>alopez : 3/26/2008<br>terry : 3/18/2008<br>wwang : 9/22/2005<br>carol : 9/21/2005<br>ckniffin : 8/29/2005<br>terry : 8/3/2005<br>tkritzer : 5/10/2005<br>terry : 4/28/2005<br>terry : 3/3/2005<br>terry : 11/3/2004<br>carol : 6/11/2004<br>terry : 6/8/2004<br>tkritzer : 1/14/2004<br>ckniffin : 1/7/2004<br>tkritzer : 12/31/2003<br>tkritzer : 12/30/2003<br>ckniffin : 12/23/2003<br>tkritzer : 10/22/2003<br>terry : 10/21/2003<br>carol : 9/25/2003<br>ckniffin : 9/18/2003<br>cwells : 9/2/2003<br>carol : 8/29/2003<br>terry : 8/27/2003<br>carol : 11/13/2002<br>ckniffin : 10/25/2002<br>ckniffin : 8/27/2002<br>mgross : 7/8/2002<br>carol : 7/16/2001<br>carol : 2/22/2000<br>mcapotos : 2/14/2000<br>terry : 2/4/2000<br>carol : 7/23/1999<br>terry : 7/19/1999<br>dholmes : 5/11/1998<br>dholmes : 5/11/1998<br>dholmes : 5/11/1998<br>jenny : 4/8/1997<br>terry : 4/4/1997<br>terry : 1/22/1997<br>terry : 1/22/1997<br>terry : 1/21/1997<br>terry : 4/22/1996<br>mark : 4/9/1996<br>mark : 4/9/1996<br>mimman : 2/8/1996<br>mark : 6/19/1995<br>pfoster : 9/13/1994<br>terry : 7/11/1994<br>mimadm : 4/19/1994<br>carol : 3/8/1994
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<strong>*</strong> 516006
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COMPLEX I, SUBUNIT ND6; MTND6
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NADH-UBIQUINONE OXIDOREDUCTASE, SUBUNIT ND6<br />
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NADH DEHYDROGENASE, SUBUNIT 6
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<strong><em>HGNC Approved Gene Symbol: MT-ND6</em></strong>
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<strong>SNOMEDCT:</strong> 39925003, 58610003, 89439007;
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<strong>ICD10CM:</strong> E88.41, H47.22;
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<p>Subunit 6 is 1 of the 7 mitochondrial DNA (mtDNA) encoded subunits (MTND1, MTND2, MTND3, MTND4L, MTND4, MTND5, MTND6) included among the approximately 41 polypeptides of respiratory Complex I (NADH:ubiquinone oxidoreductase, EC 1.6.5.3) (Shoffner and Wallace, 1995; Arizmendi et al., 1992; Walker et al., 1992; Anderson et al., 1981; Attardi et al., 1986; Chomyn et al. (1985, 1986); Wallace et al., 1986; Oliver and Wallace, 1982; Wallace et al., 1994). Complex I accepts electrons from NADH, transfers them to ubiquinone (Coenzyme Q10), and uses the energy released to pump protons across the mitochondria inner membrane. Complex I is more fully described under 516000. MTND6 has been proposed to be a component of the iron-protein fragment (Chomyn et al., 1986). </p><p>The predicted polypeptide has a molecular weight of 18.6 kD (Anderson et al., 1981). However, its apparent MW on SDS-polyacrylamide gels (PAGE) using Tris-glycine buffer is 16.7 kD (Oliver et al., 1984; Oliver and Wallace, 1982; Wallace et al., 1986), and the apparent MW on urea-phosphate gels is also close to the predicted molecular weight (Chomyn et al., 1986). </p>
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<strong>Mapping</strong>
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<p>MTND6 is encoded by the cytosine-rich light (L) strand of the mtDNA and located between nucleotide pairs (nps) 14149 and 14673 (Anderson et al., 1981; Wallace et al., 1994). It is maternally inherited along with the mtDNA (Giles et al., 1980; Case and Wallace, 1981). </p>
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<strong>Gene Structure</strong>
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<p>The MTND6 polypeptide encompasses 524 nps of continuous coding sequence. The gene contains no introns, begins with the AUG methionine start codon and ends with a UCG codon which has been proposed as the stop signal. The mRNA has a 3-prime noncoding sequence which includes 1811 nps corresponding to the anti-sense of the MTND5 coding sequence and may also extend through the tRNALeu(CUN), tRNASer(AGY), tRNAHis, and MTND4 genes, ending at tRNAArg. It is transcribed as a part of the large polycistronic L-strand transcript and is flanked on the 5-prime end by the tRNAGlu. Processing occurs at tRNAGlu and tRNAArg to give the stable L-strand transcript 3 (Anderson et al., 1981; Ojala et al., 1981; Attardi et al., 1982; Montoya et al., 1981; Wallace et al., 1994). Further processing at tRNALeu(CUN) could give a mRNA equivalent in length to the H-strand transcript 5 for MTND5. </p><p>Temperley et al. (2010) demonstrated that human mitoribosomes do invoke -1 frameshift at the AGA and AGG codons predicted to terminate the 2 ORFs in MTCO1 (516030) and MTND6, respectively. As a consequence, both ORFs terminate in the standard UAG codon, necessitating the use of only a single mitochondrial release factor. </p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<p>Restriction site polymorphisms have been identified at the following nucleotide position for the indicated enzymes (where '+' = site gain, '-' = site loss relative to the reference sequence, Anderson et al., 1981): Alu I: -14304, +14322, +14509; BamHI: -14258; Dde I: +14385, +14394, -14608; Hae III: +14279; HincII: -14199, +14648/15765; HinfI: +14268, -14368; Mbo I: -14259, +14279; Msp I: +14567;; Rsa I: +14347; Taq I: +14050/14366, +14168 (Wallace et al., 1994). </p><p>Several allelic variants have been reported for MTND6, most associated with Leber hereditary optic neuropathy (LHON): MTND6*LHON14484C (516006.0001), MTND6*LDYT14459A (516006.0002), and MTND6*LDYT14596A (516006.0003). Ravn et al. (2001) identified a mutation, MTND6*MELAS14453A (516006.0005), associated with MELAS syndrome (540000). </p><p>Most mtDNA mutations that cause human disease are mild to moderately deleterious, yet many random mtDNA changes would be expected to be severe. To determine the fate of the more severe mtDNA mutations, Fan et al. (2008) introduced mtDNAs containing 2 mutations that affect oxidative phosphorylation, one mild and one severe, into the female mouse germ line. The severe mutation, 13885insC, created a frameshift mutation in the ND6 gene. When homoplasmic, this mutation inactivates oxidative phosphorylation complex I. The mild mutation was a missense mutation, T6589C, in the cytochrome c oxidase subunit 1 gene (COI; 516030) that converted the highly conserved valine at codon 421 to alanine (V421A). When homoplasmic, this mutation reduces the activity of oxidative phosphorylation complex IV by 50%. Fan et al. (2008) observed that the severe ND6 mutation was selectively eliminated during oogenesis within 4 generations, whereas the milder COI mutation was retained throughout multiple generations even though the offspring consistently developed mitochondrial myopathy and cardiomyopathy. Thus, Fan et al. (2008) concluded that severe mitochondrial DNA mutations appear to be selectively eliminated from the female germ line, thereby minimizing their impact on population fitness. </p><p>Piccoli et al. (2008) presented evidence that mutations in the MTND6 gene (516006.0008) may modify the onset and severity of Parkinson disease (see, e.g., PARK6, 605909) caused by nuclear mutations. See also 556500 for a discussion of Parkinson disease associated with mutations in mitochondrial genes. </p><p>In an oncocytic tumor (553000) of the adnexal lacrimal glands of the conjunctiva, Bartoletti-Stella et al. (2011) analyzed the entire mtDNA sequence and identified a frameshift mutation in MTND6 (516006.0009). </p>
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<strong>Animal Model</strong>
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<p>Ishikawa et al. (2008) used cytoplasmic hybrid (cybrid) technology to replace the endogenous mtDNA in a mouse tumor cell line that was poorly metastatic with mtDNA from a cell line that was highly metastatic, and vice versa. Using assays of metastasis in mice, they found that the recipient tumor cells acquired the metastatic potential of the transferred mtDNA. The mtDNA conferring high metastatic potential contained G13997A and 13885insC mutations in the gene encoding NADH dehydrogenase subunit 6 (ND6). These mutations produced a deficiency in respiratory complex I activity and were associated with overproduction of reactive oxygen species. Pretreatment of the highly metastatic tumor cells with reactive oxygen species scavengers suppressed their metastatic potential in mice. Ishikawa et al. (2008) concluded that mtDNA mutations can contribute to tumor progression by enhancing the metastatic potential of tumor cells. </p>
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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>9 Selected Examples):</strong>
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</h4>
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<p />
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<strong>.0001 LEBER OPTIC ATROPHY</strong>
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</h4>
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MTND6, LHON14484C
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SNP: rs199476104,
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ClinVar: RCV000010325, RCV000144018, RCV000223709, RCV003162238, RCV004814873, RCV004814874
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<p>This allele changes the weakly conserved methionine at amino acid 64 to a valine (M64V). It is found in approximately 15% of Leber optic atrophy (LHON; 535000) patients, but has not been observed in any controls (less than 0.4%). It generally occurs in association with other LHON mutations. In one large Australian pedigree manifesting LHON and neurological disease, this allele occurred together with MTND1*LHON4160C (516000.0002). In most other pedigrees, the MTND6*LHON14484C allele is found together with MTND5*LHON13708A (516005.0001) in most LHON pedigrees, MTCYB*LHON15257A (516020.0001) or MTND1*LHON3394C (516000.0004) in a subset of these, and MTCYB*LHON15812A (516005.0001) and in one case MTND2*LHON5244A (516001.0002) in a subset of the MTCTB*LHON15257A pedigrees. The MTND6*LHON14484C + MTND1*LHON4160C pedigree is homoplasmic, with 76% of the maternal relatives affected, of which 54% are males. In the other MTND1*LHON 4160C pedigrees, the MTND6*LHON14484C pedigrees have all been homoplasmic except one, and between 27 and 80% of maternal relatives are affected, 68% of these being males. Patients with this mutation have an unusually high predilection for visual recovery (37%) (Brown et al., 1992; Johns et al. (1992, 1993); Mackey and Howell, 1992). </p><p>Brown et al. (1997) demonstrated that the 14484C mutation, unlike the other 2 primary LHON mutations (3460 and 11778), is not distributed on the phylogeny in proportion to the frequencies of the major Caucasian mtDNA haplogroups found in North America. The 14484 mutation was shown to occur on the haplogroup J background more frequently than expected, consistent with the observation that approximately 75% of worldwide 14484-positive LHON patients occur in association with haplogroup J. The 11778 mutation (516003.0001) also exhibited a moderate clustering on haplogroup J. Their finding suggested a pathogenic role for a subset of LHON secondary mutations and their interaction with primary mutations, and provides support for a polygenic model for LHON expression in some cases. </p><p>Carelli et al. (1998) described LHON in a patient of North African origin carrying the 14484 mutation of the ND6 gene. </p><p>Macmillan et al. (2000) analyzed 27 independently referred French-Canadian families with LHON and the 14484T-C mutation, all of which were homoplasmic for the 14484T-C mutation. They found 8 homoplasmic transition mutations (16069C-T, 16126T-C, 16213G-A, 73A-G, 185G-A, 228G-A, 263A-G, and 295C-T), compared with the Cambridge sequence of the Sanger group (Anderson et al., 1981), in the families with the 14484T-C mutation. Of the 27 families analyzed, 26 shared identical substitutions at all 8 sites that were different from the Cambridge sequence. Six of these mutations were found only in families with the 14484T-C mutation and not in either the family with 11778G-A or the family without LHON. The data were interpreted as demonstrating that French-Canadian families with LHON and the 14484T-C mutation probably share the same maternal lineage and suggested that they may all have been derived from a single founder woman. </p><p>The first report of LHON in French Canadians dated from 1970, when a large pedigree from southwestern Quebec was described by Brunette and Bernier (1970). A high rate (19.5%) of spontaneous recovery was observed in this large kindred: 4 patients regained a visual acuity of 20/50 or better in at least 1 eye and 6 regained bilateral normal vision. </p><p>Nishioka et al. (2003) identified the 14484T-C mutation in a 6-generation Indonesian LHON family. All of the maternal lineages had the 14484T-C mutation in homoplasmic form. Penetrance of the disease (33.3%) and male predominance (3:1) was similar to other worldwide LHON with the 14484T-C mutation. The incidence of offspring born to affected mothers was no different from that of unaffected mothers, and the age distribution of cases was no higher than that of asymptomatic carriers. Eight secondary mutations were sought but not detected. Patients of this family belonged to haplogroup M. These findings supported the idea that the mtDNA backgrounds involved in the expression of LHON mutations in southeast Asians are different from those of Europeans. </p><p>In platelet submitochondrial particles from 9 individuals with the 14484T-C mutation, Carelli et al. (1999) found no difference in overall complex I activity compared to controls. However, in the particles with the mutation, they detected significantly increased sensitivity to 2 inhibitors at the ubiquinol product site, myxothiazol and nonylbenzoquinol. The mutation affects the highly conserved helix C, the interaction site of ubiquinol products. Carelli et al. (1999) noted that the biochemical defect caused by the 14484T-C change resembles that reported for the ND4 11778 mutation (516003.0001). </p><p>Howell et al. (2003) determined the complete mtDNA sequences of 63 Dutch pedigrees with LHON, 56 of which carried 1 of the classic LHON mutations at nucleotide 3460 (516000.0001), 11778 (516003.0001), or 14484. The most striking incidence in which the mtDNA was either identical or related by descent was a haplogroup J mtDNA that carried the 14484 LHON mutation. In 7 of the pedigrees, 4 different but related mitochondrial genotypes were identified. The control region of the founder sequence for these Dutch pedigrees with LHON matched the control region sequence that Macmillan et al. (2000) identified in the founder mtDNA of French-Canadian pedigrees with LHON. In addition, Howell et al. (2003) obtained a perfect match between the Dutch 14484 founder sequence and the complete mtDNA sequences of 2 Canadian pedigrees with LHON. These results indicated that these Dutch and French-Canadian 14484 pedigrees with LHON shared a common ancestor, that the single origin of the 14484 mutation in this 'megalineage' occurred before the year 1600, and that there is a 14484/haplogroup J founder effect. Howell et al. (2003) estimated that this lineage (including the 14484 LHON mutation) arose 900 to 1,800 years ago. </p><p>Using genealogic reconstructions of maternal lineages, Laberge et al. (2005) identified a woman married in Quebec City in 1669 as the shared female ancestor for 11 of 13 French Canadian individuals with the T14484C mutation who were not previously known to be related. The individuals carried identical mitochondrial haplogroups. </p><p>Elliott et al. (2008) determined the frequency of 10 mitochondrial point mutations in 3,168 neonatal cord blood samples from sequential live births in North Cumbria in England, analyzing matched maternal blood samples to estimate the de novo mutation rate. Mitochondrial DNA mutations were detected in 15 offspring (0.54%, 95% confidence interval = 0.30-0.89%). Of these live births, 0.00107% (95% confidence interval = 0.00087-0.0127) harbored a mutation not detected in the mother's blood, providing an estimate of the de novo mutation rate. The mitochondrial 14484T-C mutation was only found on subbranches of mtDNA haplogroup J. Elliott et al. (2008) concluded that at least 1 in 200 healthy humans harbors a pathogenic mitochondrial DNA mutation that potentially causes disease in the offspring of female carriers. The exclusive detection of mitochondrial 1448T-C on haplogroup J implicates the background mitochondrial DNA haplotype in mutagenesis. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 LEBER OPTIC ATROPHY AND DYSTONIA</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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LEBER OPTIC ATROPHY, INCLUDED<br />
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LEIGH SYNDROME DUE TO MITOCHONDRIAL COMPLEX I DEFICIENCY, INCLUDED
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</span>
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<span class="mim-text-font">
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MTND6, LDYT14459A
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<br />
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SNP: rs199476105,
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ClinVar: RCV000010326, RCV000010327, RCV000010328, RCV000144019, RCV001796715, RCV004696634
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</span>
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<span class="mim-text-font">
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<p>In affected members of a large Hispanic family with Leber optic atrophy and dystonia (500001), Jun et al. (1994) identified a heteroplasmic 14459G-A transition in the MTND6 gene. This mutation results in an ala72-to-val (A72V) substitution. Leber optic atrophy predominated in the early generations and dystonia together with bilateral striatal necrosis was found in later generations. Among members of the later generations, 48% of the maternal relatives manifested dystonia, 10% LHON, and 3% LHON and dystonia. </p><p>Shoffner et al. (1995) identified a heteroplasmic 14459G-A mutation in a mother and daughter with isolated LHON (535000) and in an unrelated girl with childhood-onset generalized dystonia. The daughter in the first family showed unilateral lesions in the basal ganglia on MRI, whereas the child in the second family had extensive bilateral lesions in the basal ganglia. Although the child with dystonia was severely affected, with dysarthria, quadriparesis, scoliosis, and pes cavus, intelligence was normal. The mother in the first family showed 50% heteroplasmy for the mutation in leukocytes, whereas her daughter showed homoplasmy in leukocytes and muscle. The girl in the second family showed 50% heteroplasmy for the mutation in skeletal muscle. </p><p>In 3 patients with Leigh syndrome (500017) from 2 unrelated families, Kirby et al. (2000) identified the 14459G-A mutation in the MTND6 gene. There was no evidence of Leber optic atrophy or dystonia. </p><p>Gropman et al. (2004) reported a family with a homoplasmic 14459G-A mtDNA mutation and a broad spectrum of clinical manifestations due to complex I deficiency (252010). The proband had anarthria, dystonia, spasticity, and mild encephalopathy, and an MRI revealed bilateral, symmetric basal ganglia lucencies associated with cerebral and systemic lactic acidosis. Among other family members with the mutation, some were asymptomatic and others were symptomatic with variable clinical and laboratory features, confirming the heterogeneous phenotype of homoplasmic 14459G-A mtDNA mutations, even within the same family. </p><p>Watanabe et al. (2006) identified the 14459G-A mutation in 2 Japanese sisters with childhood-onset dystonia, mental deterioration, adult-onset LHON, and basal ganglia lesions. </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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<h4>
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<span class="mim-font">
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<strong>.0003 LEBER OPTIC ATROPHY AND DYSTONIA</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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MTND6, LDYT14596A
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<br />
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SNP: rs387906424,
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ClinVar: RCV000010329, RCV000055704, RCV004791208
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a large Dutch kindred in which Leber optic atrophy was associated with hereditary spastic dystonia (see 500001 and 535000) in some members whereas only 1 type of abnormality was found in others, De Vries et al. (1996) found 2 previously unreported mtDNA mutations. One was a heteroplasmic A-to-G transition at nucleotide position 11696 in the ND4 gene (516003.0003) that resulted in the substitution of an isoleucine for valine at amino acid position 312. A second mutation, a homoplasmic T-to-A transition at nucleotide position 14596 in the ND6 gene, resulted in the substitution of a methionine for isoleucine at amino acid residue 26. Biochemical analysis of a muscle biopsy showed severe complex I deficiency. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 LEBER OPTIC ATROPHY</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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MTND6, LHON14495G
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<br />
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SNP: rs199476106,
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ClinVar: RCV000010330, RCV002260588
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<div>
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<span class="mim-text-font">
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<p>Chinnery et al. (2001) described 2 pedigrees with Leber optic atrophy (535000) that harbored the same novel point mutation in the MTND6 gene, i.e., a 14495A-G change resulting in a leu-to-ser substitution. The mutation was heteroplasmic in both families, and sequencing of the mitochondrial genome confirmed that the mutation arose on 2 independent occasions. </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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<h4>
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<span class="mim-font">
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<strong>.0005 MELAS SYNDROME</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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MTND6, MELAS14453A
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<br />
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SNP: rs199476107,
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ClinVar: RCV000010331, RCV000855109, RCV002260589
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a sporadic case of MELAS syndrome (540000), Ravn et al. (2001) identified a heteroplasmic G-to-A transition at nucleotide 14453 of the ND6 gene, resulting in an ala74-to-val (A74V) substitution. The patient was a 7-year-old girl with normal development until the age of 2 years. Between 2 and 3 years of age, she had episodes of vomiting followed by ketotic acidosis. She developed myoclonic epilepsy, general weakness, and ataxia with intermitting dystonia. Magnetic resonance scans showed cerebellar hypoplasia and multiple infarctions in both hemispheres. A muscle biopsy revealed lipid storage myopathy with normal mitochondria on electron microscopy. The patient developed episodes of lethargy, lactic acidosis, and alternating uniparesis. Ophthalmologic examination revealed no sign of atrophy of the optic nerve but abolished visual evoked potentials (VEP). The mother was healthy, with no history of a mitochondrial disorder. Mitochondrial enzyme analysis in the patient showed a decreased activity of complex I in muscle. Sequencing of the entire mtDNA, except part of the D loop, revealed heteroplasmy for the 14453G-A mutation in 82% of the mtDNA of the patient's muscle and 78% in blood. The mutation was not detected in the blood of the mother nor in 50 healthy controls. In addition to the 14453G-A mutation, Ravn et al. (2001) identified 2 other homoplasmic mutations in the mtDNA of their patient, 5628T-C in the MTTA gene (590000) and 13535A-G in the MTND5 gene (516005), which might have contributed to the observed decrease in activity of complex I and the severe phenotype of the patient. </p>
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</span>
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</div>
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<div>
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<br />
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 LEBER OPTIC ATROPHY</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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MTND6, LHON14482A
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<br />
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SNP: rs199476108,
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ClinVar: RCV000010332, RCV002260590
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 maternally related males with Leber optic atrophy (535000) characterized by visual recovery, Valentino et al. (2002) identified a homoplasmic 14482C-A transversion in the MTND6 gene, resulting in a met64-to-ile change in an area known to be a mutation hotspot. Sequencing of the area showed that the mutation was found on a haplogroup J mtDNA background, similar to the 14484T-C mutation (516006.0001), which results in a met64-to-val substitution. Methionine, isoleucine, and valine are all hydrophobic. </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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<h4>
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<span class="mim-font">
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<strong>.0007 LEIGH SYNDROME DUE TO MITOCHONDRIAL COMPLEX I DEFICIENCY</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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STRIATAL NECROSIS, BILATERAL, WITH DYSTONIA, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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MTND6, 14487T-C
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<br />
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SNP: rs199476109,
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ClinVar: RCV000010333, RCV000010334, RCV000144020, RCV002247307, RCV003162239
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a male infant with Leigh syndrome (500017), Ugalde et al. (2003) identified a heteroplasmic 14487T-C transition in the MTND6 gene, resulting in a met63-to-val (M63V) substitution. The patient presented at 4 months of age with tonic-clonic seizures, and was later found to have motor retardation, hypotonia, deafness, pyramidal and extrapyramidal tract signs, and episodic brainstem events with oculomotor palsies, strabismus, and recurrent apnea. Laboratory studies showed lactic acidemia and basal ganglia lesions. He died at age 7 months. The patient's mother had 24% mutant load in blood, and the patient had 65% mutant load in muscle and liver, and 86% mutant load in fibroblasts. Further studies showed that the mutation occurred in the most conserved transmembrane helix of the protein and caused an impaired assembly of complex I (252010). Ugalde et al. (2003) commented on the severe phenotypic expression of the M63V mutation. </p><p>In 2 unrelated males with progressive generalized dystonia and bilateral striatal necrosis beginning at ages 4 and 6 years, respectively, Solano et al. (2003) identified the M63V mutation. In 1 patient, there was a high proportion of mutant mtDNA in muscle (93%) and in blood (67%). His unaffected mother showed 26% heteroplasmy in blood. Biochemical analysis showed isolated complex I deficiency. Solano et al. (2003) noted that other reports (e.g., Funalot et al., 2002) had found association between mutation in MTND6 and dystonia and bilateral striatal necrosis. </p>
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<h4>
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<span class="mim-font">
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<strong>.0008 PARKINSON DISEASE 6, MODIFIER OF</strong>
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<span class="mim-text-font">
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MTND6, 14319T-C
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<br />
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SNP: rs199476110,
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ClinVar: RCV000010335, RCV000855091
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<p>In a patient with early-onset Parkinson disease (PARK6; 605909) due to a homozygous mutation in the PINK1 gene (608309.0002), Piccoli et al. (2008) identified a homoplasmic 14319T-C mutation in the MTND6 gene and a homoplasmic mutation in the MTND6 gene (516006.0010). The 14319T-C mutation results in an asn119-to-asp (N119D) substitution in the fifth of 6 predicted transmembrane helices. The patient had onset at age 22 years. His mother, who was heterozygous for the PINK1 mutation, was also homoplasmic for both mitochondrial mutations and showed disease onset at age 53. The father was heterozygous for the PINK1 mutation only and unaffected at age 79. Biochemical studies of the proband's fibroblasts showed mitochondrial dysfunction, with decreased amounts of cytochrome c oxidase, impaired complex I activity, and increased hydrogen peroxide generation. Piccoli et al. (2008) concluded that the presence of the mitochondrial mutations in combination with the PINK1 mutation may have accelerated the onset of the disease. </p>
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<h4>
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<span class="mim-font">
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<strong>.0009 ONCOCYTOMA</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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MTND6, 1-BP INS, 14249C
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<br />
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SNP: rs869312882,
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ClinVar: RCV000210344
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<span class="mim-text-font">
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<p>In an oncocytic tumor (553000) of the adnexal lacrimal glands of the conjunctiva, Bartoletti-Stella et al. (2011) identified a 1-bp insertion (14249insC) in the MTND6 gene, predicted to cause a frameshift and hamper assembly of complex I. The mutation appeared to be heteroplasmic in the tumor, which was confirmed by immunohistochemical analysis showing that MTND6 expression was much fainter in the oncocytic neoplasm compared to nonneoplastic tissue. Ki67 staining revealed a low proliferation index of 1.8%, consistent with the benign nature of the case. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Ragan (1987)
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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>REFERENCES</strong>
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<strong>Sequence analysis of the mitochondrial genomes from Dutch pedigrees with Leber hereditary optic neuropathy.</strong>
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[PubMed: 12736867]
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<p class="mim-text-font">
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Ishikawa, K., Takenaga, K., Akimoto, M., Koshikawa, N., Yamaguchi, A., Imanishi, H., Nakada, K., Honma, Y., Hayashi, J.-I.
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<strong>ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis.</strong>
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Science 320: 661-664, 2008.
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[PubMed: 18388260]
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Johns, D. R., Heher, K. L., Miller, N. R., Smith, K. H.
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<strong>Leber's hereditary optic neuropathy. Clinical manifestations of the 14484 mutation.</strong>
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Arch. Ophthal. 111: 495-498, 1993.
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[PubMed: 8470982]
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Johns, D. R., Neufeld, M. J., Park, R. D.
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<strong>An ND-6 mitochondrial DNA mutation associated with Leber hereditary optic neuropathy.</strong>
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Biochem. Biophys. Res. Commun. 187: 1551-1557, 1992.
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[PubMed: 1417830]
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[Full Text: https://doi.org/10.1016/0006-291x(92)90479-5]
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</p>
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<li>
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<p class="mim-text-font">
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Jun, A. S., Brown, M. D., Wallace, D. C.
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<strong>A mitochondrial DNA mutation at nucleotide pair 14459 of the NADH dehydrogenase subunit 6 gene associated with maternally inherited Leber hereditary optic neuropathy and dystonia.</strong>
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|
Proc. Nat. Acad. Sci. 91: 6206-6210, 1994.
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[PubMed: 8016139]
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[Full Text: https://doi.org/10.1073/pnas.91.13.6206]
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</p>
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<li>
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<p class="mim-text-font">
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Kirby, D. M., Kahler, S. G., Freckmann, M.-L., Reddihough, D., Thorburn, D. R.
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Marla J. F. O'Neill - updated : 9/15/2011<br>Ada Hamosh - updated : 2/1/2010<br>Cassandra L. Kniffin - updated : 10/6/2008<br>Ada Hamosh - updated : 9/8/2008<br>Ada Hamosh - updated : 6/17/2008<br>Cassandra L. Kniffin - updated : 4/4/2008<br>Ada Hamosh - updated : 3/18/2008<br>Marla J. F. O'Neill - updated : 9/22/2005<br>Victor A. McKusick - updated : 4/28/2005<br>Marla J. F. O'Neill - updated : 6/8/2004<br>Cassandra L. Kniffin - updated : 1/7/2004<br>Cassandra L. Kniffin - updated : 12/23/2003<br>Victor A. McKusick - updated : 10/21/2003<br>Cassandra L. Kniffin - updated : 9/18/2003<br>Victor A. McKusick - updated : 8/27/2003<br>Michael B. Petersen - updated : 7/8/2002<br>Jane Kelly - updated : 7/16/2001<br>Victor A. McKusick - updated : 2/4/2000<br>Victor A. McKusick - updated : 7/19/1999<br>Victor A. McKusick - updated : 4/8/1997<br>Douglas C. Wallace - updated : 4/8/1994
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