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- *516003 - COMPLEX I, SUBUNIT ND4; MTND4
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- OMIM
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<p>
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<span class="h4">*516003</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="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<a href="/allelicVariants/516003">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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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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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=ENSG00000198886;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-ND4" 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=4538" 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=516003" 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="mimDna">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000198886;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=516003" 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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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.proteinatlas.org/search/MT-ND4" 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/128748,506833,251831116" 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/P03905" 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=4538" 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=ENSG00000198886;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-ND4" 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-ND4" 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+4538" 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-ND4" 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:4538" 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/4538" 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:7459" 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-nd4" 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=516003[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=516003[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/ENSG00000198886" 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-ND4" 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-ND4" 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-ND4&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/PA31263" 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 style="display: table-row">
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<div style="display: table-cell;">Animal Models</div>
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</a>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:7459" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0262952.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:102498" 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-ND4#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:102498" 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/4538/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=4538" 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;">Cell Lines</div>
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:516003" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:4538" 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-ND4&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>
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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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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 237988006, 39925003, 58610003<br />
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<strong>ICD10CM:</strong> E88.41, H47.22<br />
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">ICD+</a>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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516003
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</span>
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</span>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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COMPLEX I, SUBUNIT ND4; MTND4
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</span>
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</h3>
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</div>
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<div>
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<br />
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<div>
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<h4>
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<span class="mim-font">
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NADH-UBIQUINONE OXIDOREDUCTASE, SUBUNIT ND4<br />
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NADH DEHYDROGENASE, SUBUNIT 4
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</h4>
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<br />
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=MT-ND4" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">MT-ND4</a></em></strong>
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<div>
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<br />
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<a id="text" class="mim-anchor"></a>
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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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</span>
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</h4>
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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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</span>
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</h4>
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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>Subunit 4 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="#63" 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. (7th ed.)</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="#72" 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, 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="#13" class="mim-tip-reference" title="Chomyn, A., Mariottini, P., Cleeter, M. W. J., Ragan, C. I., Matsuno-Yagi, A., Hatefi, Y., Doolittle, R. F., 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="#12" 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="#75" 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="#56" 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="#73" 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 out across the mitochondrial inner membrane. Complex I is more fully described in <a href="/entry/516000">516000</a>. MTND4 is probably a component of the hydrophobic protein fragment (<a href="#61" class="mim-tip-reference" title="Ragan, C. I. <strong>Structure of NADH-ubiquinone reductase (Complex I).</strong> Curr. Top. Bioenerg. 15: 1-36, 1987."None>Ragan, 1987</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3518425+3921850+7219534+1426273+1518044+3764430+6955589+3472707" 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>MTND4 is encoded by the guanine-rich heavy (H) strand of the mtDNA and located between nucleotide pair (nps) 10760 and 12137 (<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="#73" 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="#21" 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="#9" 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 MTND4 gene encompasses 1377 nps of continuous coding sequence. It is part of a bicistronic mRNA, occupying the 3-prime end while its companion gene, MTND4L, occupies the 5-prime end. The MTND4 protein coding sequence begins 291 np from the 5-prime end of the mRNA, with its seven 5-prime nucleotides overlapping with the last 2 codons and termination codon of MTND4L. The MTND4 open reading frame is continuous without introns and ends with the U of the UAA termination codon (<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="#73" 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="#54" 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>). The bicistronic MTND4L + MTND4 mRNA is transcribed as a part of the polycistronic H-strand transcript, flanked by tRNA Arg at the 5-prime end and tRNA His at the 3-prime end. These tRNAs are cleaved from the transcript freeing transcript 7, the MTND4L + MTND4 mRNA. The mRNA is then polyadenylated completing the MTND4 termination codon (<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="#54" 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="#73" 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/?term=7219534+7219536+7140372" 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 predicted polypeptide molecular weight is 51.4 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, the apparent molecular weight upon SDS-polyacrylamide gel electrophoresis (PAGE) using Tris-glycine buffer is 36.5 kD (<a href="#75" 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="#55" 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>) whereas with urea-phosphate buffer it is 36 to 39 kD (<a href="#13" class="mim-tip-reference" title="Chomyn, A., Mariottini, P., Cleeter, M. W. J., Ragan, C. I., Matsuno-Yagi, A., Hatefi, Y., Doolittle, R. F., 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">Chomyn et al., 1985</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7219534+3518425+6438810+3921850" 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: +11100, +11321, +11350, -11362, +11425, +11469, -11576, +11806, +11892; Ava II: -11577; Dde I: +11074, +11146, +11793; Hae II: +11001, +11968; Hae III: +11092, +11313, +11329/11690, +11390/13633; Hha I: +11002, -11691, +11969; HincII: +12026; HinfI: +10806, -10830, -10971, -11403, +12008; Hpa I: +12026; Mbo I: +10934, -11922, +11431, +11439; Msp I: +11161, -11688, -12123; Rsa I: +11063, -11447, -11546, +11900, +11974; Taq I: +10893, +11924 (<a href="#73" 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>The major MTND4 allele is a mutation at np 11778 (MTND4*LHON11778A; <a href="#0001">516003.0001</a>) which causes Leber hereditary optic neuropathy (LHON; <a href="/entry/535000">535000</a>) (<a href="#74" class="mim-tip-reference" title="Wallace, D. C., Singh, G., Lott, M. T., Hodge, J. A., Schurr, T. G., Lezza, A. M., Elsas, L. J., Nikoskelainen, E. K. <strong>Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy.</strong> Science 242: 1427-1430, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3201231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3201231</a>] [<a href="https://doi.org/10.1126/science.3201231" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3201231">Wallace et al., 1988</a>). <a href="#58" class="mim-tip-reference" title="Pilz, D., Quarrell, O. W. J., Jones, E. W. <strong>Mitochondrial mutation commonly associated with Leber's hereditary optic neuropathy observed in a patient with Wolfram syndrome (DIDMOAD).</strong> J. Med. Genet. 31: 328-330, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8071960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8071960</a>] [<a href="https://doi.org/10.1136/jmg.31.4.328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8071960">Pilz et al. (1994)</a> observed the Wolfram syndrome (<a href="/entry/598500">598500</a>) in a man with this mutation. A combination with another undetected mutation in the mitochondrial genome or with a mutation in the nuclear genome or coincidental occurrence with the autosomal form of the disorder (<a href="/entry/222300">222300</a>) in heterozygous or homozygous form may account for the finding. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8071960+3201231" 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="#36" class="mim-tip-reference" title="Kogelnik, A. M., Lott, M. T., Brown, M. D., Navathe, S. B., Wallace, D. C. <strong>MITOMAP: a human mitochondrial genome database.</strong> Nucleic Acids Res. 24: 177-179, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8594574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8594574</a>] [<a href="https://doi.org/10.1093/nar/24.1.177" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8594574">Kogelnik et al. (1996)</a> described a comprehensive database, MITOMAP, for human mitochondrial DNA. MITOMAP uses the mtDNA sequence information on mitochondrial genome structure and function, pathogenic mutations and their clinical characteristics, population-associated variation, and gene-gene interactions. MITOMAP not only provides a valuable reference for the mitochondrial biologist but also provides a model for development of information storage and retrieval systems for other components of the human genome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8594574" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=516003[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199476112 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476112;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=rs199476112" 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=rs199476112" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>The allele changes the highly conserved arginine at amino acid 340 to a histidine (R340H). This allele accounts for over 50% of Leber hereditary optic neuropathy (LHON; <a href="/entry/535000">535000</a>) cases among Caucasians and over 90% of the cases in Asians. The mutation has not been observed in random population controls, may be either homoplasmic or heteroplasmic within families, and has been shown to have arisen multiple times on different mtDNA haplotypes in association with the disease (<a href="#74" class="mim-tip-reference" title="Wallace, D. C., Singh, G., Lott, M. T., Hodge, J. A., Schurr, T. G., Lezza, A. M., Elsas, L. J., Nikoskelainen, E. K. <strong>Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy.</strong> Science 242: 1427-1430, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3201231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3201231</a>] [<a href="https://doi.org/10.1126/science.3201231" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3201231">Wallace et al., 1988</a>; <a href="#64" class="mim-tip-reference" title="Singh, G., Lott, M. T., Wallace, D. C. <strong>A mitochondrial DNA mutation as a cause of Leber's hereditary optic neuropathy.</strong> New Eng. J. Med. 320: 1300-1305, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2566116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2566116</a>] [<a href="https://doi.org/10.1056/NEJM198905183202002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2566116">Singh et al., 1989</a>). In families harboring this mutation, approximately 33 to 60% of the maternal relatives are affected and of these, about 80% are males. Visual recovery is seen in only 4% of cases (see LHON Table, MIM11 foreword section) (<a href="#5" class="mim-tip-reference" title="Bolhuis, P. A., Bleeker-Wagemakers, E. M., Ponne, N. J., Van Schooneveld, M. J., Westerveld, A., Van den Bogert, C., Tabak, H. F. <strong>Rapid shift in genotype of human mitochondrial DNA in a family with Leber's hereditary optic neuropathy.</strong> Biochem. Biophys. Res. Commun. 170: 994-997, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2390098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2390098</a>] [<a href="https://doi.org/10.1016/0006-291x(90)90490-e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2390098">Bolhuis et al., 1990</a>; <a href="#7" class="mim-tip-reference" title="Carducci, C., Leuzzi, V., Scuderi, M., De Negri, A. M., Gabrieli, C. B., Antonozzi, I., Pontecorvi, A. <strong>Mitochondrial DNA mutation in an Italian family with Leber hereditary optic neuropathy.</strong> Hum. Genet. 87: 725-727, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1937476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1937476</a>] [<a href="https://doi.org/10.1007/BF00201733" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1937476">Carducci et al., 1991</a>; <a href="#10" class="mim-tip-reference" title="Cavelier, L., Gyllensten, U., Dahl, N. <strong>Intrafamilial variation in Leber hereditary optic neuropathy revealed by direct mutation analysis.</strong> Clin. Genet. 43: 69-72, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8448903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8448903</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1993.tb04429.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8448903">Cavelier et al., 1993</a>; <a href="#14" class="mim-tip-reference" title="Cortelli, P., Montagna, P., Avoni, P., Sangiorgi, S., Bresolin, N., Moggio, M., Zaniol, P., Mantovani, V., Barboni, P., Barbiroli, B., Lugaresi, E. <strong>Leber's hereditary optic neuropathy: genetic, biochemical, and phosphorus magnetic resonance spectroscopy study in an Italian family.</strong> Neurology 41: 1211-1215, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1866007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1866007</a>] [<a href="https://doi.org/10.1212/wnl.41.8.1211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1866007">Cortelli et al., 1991</a>; <a href="#15" class="mim-tip-reference" title="Cullom, M. E., Heher, K. L., Miller, N. R., Savino, P. J., Johns, D. R. <strong>Leber's hereditary optic neuropathy masquerading as tobacco-alcohol amblyopia..</strong> Arch. Ophthal. 111: 1482-1485, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8240101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8240101</a>] [<a href="https://doi.org/10.1001/archopht.1993.01090110048021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8240101">Cullom et al., 1993</a>; <a href="#20" class="mim-tip-reference" title="Erickson, C. E., Castora, F. J. <strong>PCR amplification using a single cell allows the detection of the mtDNA lesion associated with Leber's hereditary optic neuropathy.</strong> Biochim. Biophys. Acta 1181: 77-82, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8457609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8457609</a>] [<a href="https://doi.org/10.1016/0925-4439(93)90093-g" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8457609">Erickson and Castora, 1993</a>; Hiida et al. (<a href="#24" class="mim-tip-reference" title="Hiida, Y., Mashima, Y., Oguchi, Y., Uemura, Y., Kudoh, J., Sakai, K., Shimizu, N. <strong>Mitochondrial DNA analysis of Leber's hereditary optic neuropathy.</strong> Jpn. J. Ophthal. 35: 102-106, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1895564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1895564</a>]" pmid="1895564">1991</a>, <a href="#23" class="mim-tip-reference" title="Hiida, Y., Mashima, Y., Oguchi, Y., Kudoh, J., Sakai, K., Shimizu, N. <strong>Analysis of mitochondrial DNA in Leber's hereditary optic neuropathy. In: Yoshida, T. O.; Wilson, J. M. (eds.): Molecular Approaches to the Study and Treatment of Human Diseases.</strong> Amsterdam: Elsevier Science Publishers (pub.) 1992."None>1992</a>); <a href="#25" class="mim-tip-reference" title="Holt, I. J., Miller, D. H., Harding, A. E. <strong>Genetic heterogeneity and mitochondrial DNA heteroplasmy in Leber's hereditary optic neuropathy.</strong> J. Med. Genet. 26: 739-743, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2575667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2575667</a>] [<a href="https://doi.org/10.1136/jmg.26.12.739" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2575667">Holt et al., 1989</a>; <a href="#26" class="mim-tip-reference" title="Hotta, Y., Hayakawa, M., Saito, K., Kanai, A., Nakajima, A., Fujiki, K. <strong>Diagnosis of Leber's optic neuropathy by means of polymerase chain reaction amplification.</strong> Am. J. Ophthal. 108: 601-602, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2817063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2817063</a>] [<a href="https://doi.org/10.1016/0002-9394(89)90444-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2817063">Hotta et al., 1989</a>; <a href="#27" class="mim-tip-reference" title="Howell, N., McCullough, D., Bodis-Wollner, I. <strong>Molecular genetic analysis of a sporadic case of Leber hereditary optic neuropathy (letter). (Letter)</strong> Am. J. Hum. Genet. 50: 443-446, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1734726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1734726</a>]" pmid="1734726">Howell et al., 1992</a>; <a href="#28" class="mim-tip-reference" title="Huoponen, K., Vilkki, J., Savontaus, M.-L., Aula, P., Nikoskelainen, E. K. <strong>Analysis of mitochondrial ND4 gene DNA sequence in Finnish families with Leber hereditary optic neuroretinopathy.</strong> Genomics 8: 583-585, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2286378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2286378</a>] [<a href="https://doi.org/10.1016/0888-7543(90)90049-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2286378">Huoponen et al., 1990</a>; <a href="#29" class="mim-tip-reference" title="Isashiki, Y., Nakagawa, M. <strong>Clinical correlation of mitochondrial DNA heteroplasmy and Leber's hereditary optic neuropathy.</strong> Jpn. J. Ophthal. 35: 259-267, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1770665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1770665</a>]" pmid="1770665">Isashiki and Nakagawa, 1991</a>; <a href="#35" class="mim-tip-reference" title="Johns, D. R. <strong>The molecular genetics of Leber's hereditary optic neuropathy.</strong> Arch. Ophthal. 108: 1405-1407, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2222273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2222273</a>] [<a href="https://doi.org/10.1001/archopht.1990.01070120053027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2222273">Johns, 1990</a>; <a href="#31" class="mim-tip-reference" title="Johns, D. R., Berman, J. <strong>Alternative, simultaneous complex I mitochondrial DNA mutations in Leber's hereditary optic neuropathy.</strong> Biochem. Biophys. Res. Commun. 174: 1324-1330, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1900003/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1900003</a>] [<a href="https://doi.org/10.1016/0006-291x(91)91567-v" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1900003">Johns and Berman, 1991</a>; Johns et al. (<a href="#32" 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="#33" class="mim-tip-reference" title="Johns, D. R., Smith, K. H., Miller, N. R., Sulewski, M. E., Bias, W. B. <strong>Identical twins who are discordant for Leber's hereditary optic neuropathy.</strong> Arch. Ophthal. 111: 1491-1494, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8240103/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8240103</a>] [<a href="https://doi.org/10.1001/archopht.1993.01090110057023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8240103">1993</a>); <a href="#37" class="mim-tip-reference" title="Kormann, B. A., Schuster, H., Berninger, T. A., Leo-Kottler, B. <strong>Detection of the G to A mitochondrial DNA mutation at position 11778 in German families with Leber's hereditary optic neuropathy.</strong> Hum. Genet. 88: 98-100, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1959931/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1959931</a>] [<a href="https://doi.org/10.1007/BF00204937" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1959931">Kormann et al., 1991</a>; <a href="#38" class="mim-tip-reference" title="Larsson, N. G., Andersen, O., Holme, E., Oldfors, A., Wahlstrom, J. <strong>Leber's hereditary optic neuropathy and complex I deficiency in muscle.</strong> Ann. Neurol. 30: 701-708, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1763894/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1763894</a>] [<a href="https://doi.org/10.1002/ana.410300511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1763894">Larsson et al., 1991</a>; <a href="#40" class="mim-tip-reference" title="Lott, M. T., Voljavec, A. S., Wallace, D. C. <strong>Variable genotype of Leber's hereditary optic neuropathy patients .</strong> Am. J. Ophthal. 109: 625-631, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2346190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2346190</a>] [<a href="https://doi.org/10.1016/s0002-9394(14)72429-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2346190">Lott et al., 1990</a>; <a href="#41" class="mim-tip-reference" title="Majander, A., Huoponen, K., Savontaus, M.-L., Nikoskelainen, E., Wikstrom, M. <strong>Electron transfer properties of NADH:ubiquinone reductase in the ND1/3460 and the ND4/11778 mutations of the Leber hereditary optic neuroretinopathy (LHON).</strong> FEBS Lett. 292: 289-292, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1959619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1959619</a>] [<a href="https://doi.org/10.1016/0014-5793(91)80886-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1959619">Majander et al., 1991</a>; Mashima et al. (<a href="#44" class="mim-tip-reference" title="Mashima, Y., Hiida, Y., Oguchi, Y. <strong>Remission of Leber's hereditary optic neuropathy with idebenone . (Letter)</strong> Lancet 340: 368-369, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1353825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1353825</a>] [<a href="https://doi.org/10.1016/0140-6736(92)91442-b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1353825">1992</a>, <a href="#42" class="mim-tip-reference" title="Mashima, Y., Hiida, Y., Kubota, R., Oguchi, Y., Kudoh, J., Shimizu, N. <strong>DNA diagnosis of Leber's hereditary optic neuropathy using dried blood specimens. (Letter)</strong> Am. J. Ophthal. 116: 773-774, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8250088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8250088</a>] [<a href="https://doi.org/10.1016/s0002-9394(14)73485-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8250088">1993</a>); <a href="#47" class="mim-tip-reference" title="Moorman, C. M., Elston, J. S., Matthews, P. <strong>Leber's hereditary optic neuropathy as a cause of severe visual loss in childhood.</strong> Pediatrics 91: 988-989, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8474822/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8474822</a>]" pmid="8474822">Moorman et al., 1993</a>; <a href="#49" class="mim-tip-reference" title="Nakamura, M., Fujiwara, Y., Yamamoto, M. <strong>Homoplasmic and exclusive ND4 gene mutation in Japanese pedigrees with Leber's disease.</strong> Invest. Ophthal. Vis. Sci. 34: 488-495, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8449667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8449667</a>]" pmid="8449667">Nakamura et al., 1993</a>; <a href="#52" class="mim-tip-reference" title="Newman, N. J. <strong>Leber's hereditary optic neuropathy. New genetic considerations.</strong> Arch. Neurol. 50: 540-548, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8489411/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8489411</a>] [<a href="https://doi.org/10.1001/archneur.1993.00540050082021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8489411">Newman, 1993</a>; <a href="#50" class="mim-tip-reference" title="Newman, N. J., Lott, M. T., Wallace, D. C. <strong>The clinical characteristics of pedigrees of Leber's hereditary optic neuropathy with the 11778 mutation.</strong> Am. J. Ophthal. 111: 750-762, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2039048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2039048</a>] [<a href="https://doi.org/10.1016/s0002-9394(14)76784-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2039048">Newman et al., 1991</a>; <a href="#51" class="mim-tip-reference" title="Newman, N. J., Wallace, D. C. <strong>Mitochondria and Leber's hereditary optic neuropathy.</strong> Am. J. Ophthal. 109: 726-730, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2346203/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2346203</a>] [<a href="https://doi.org/10.1016/s0002-9394(14)72445-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2346203">Newman and Wallace, 1990</a>; <a href="#53" class="mim-tip-reference" title="Norby, S. <strong>Mutation-specific PCR: a rapid and inexpensive diagnostic method, as exemplified by mitochondrial DNA analysis in Leber's hereditary optic neuropathy.</strong> DNA Cell Biol. 12: 549-552, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8101084/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8101084</a>] [<a href="https://doi.org/10.1089/dna.1993.12.549" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8101084">Norby, 1993</a>; <a href="#59" class="mim-tip-reference" title="Poulton, J., Deadman, M. E., Bronte-Stewart, J., Foulds, W. S., Gardiner, R. M. <strong>Analysis of mitochondrial DNA in Leber's hereditary optic neuropathy.</strong> J. Med. Genet. 28: 765-770, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1770533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1770533</a>] [<a href="https://doi.org/10.1136/jmg.28.11.765" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1770533">Poulton et al., 1991</a>; <a href="#64" class="mim-tip-reference" title="Singh, G., Lott, M. T., Wallace, D. C. <strong>A mitochondrial DNA mutation as a cause of Leber's hereditary optic neuropathy.</strong> New Eng. J. Med. 320: 1300-1305, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2566116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2566116</a>] [<a href="https://doi.org/10.1056/NEJM198905183202002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2566116">Singh et al., 1989</a>; <a href="#65" class="mim-tip-reference" title="Smith, K. H., Johns, D. R., Heher, K. L., Miller, N. R. <strong>Heteroplasmy in Leber's Hereditary optic neuropathy.</strong> Arch. Ophthal. 111: 1486-1490, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8240102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8240102</a>] [<a href="https://doi.org/10.1001/archopht.1993.01090110052022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8240102">Smith et al., 1993</a>; Stone et al. (<a href="#66" class="mim-tip-reference" title="Stone, E. M., Coppinger, J. M., Kardon, R. H., Donelson, J. <strong>Mae III positively detects the mitochondrial mutation associated with type I Leber's hereditary optic neuropathy.</strong> Arch. Ophthal. 108: 1417-1420, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1977373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1977373</a>] [<a href="https://doi.org/10.1001/archopht.1990.01070120065030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1977373">1990</a>, <a href="#67" class="mim-tip-reference" title="Stone, E. M., Newman, N. J., Miller, N. R., Johns, D. R., Lott, M. T., Wallace, D. C. <strong>Visual recovery in patients with Leber's hereditary optic neuropathy and the 11778 mutation.</strong> J. Clin. Neuroophthalmol. 12: 10-14, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1532593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1532593</a>]" pmid="1532593">1992</a>); <a href="#68" class="mim-tip-reference" title="Sudoyo, H., Marzuki, S., Mastaglia, F., Carroll, W. <strong>Molecular genetics of Leber's hereditary optic neuropathy: study of a six-generation family from Western Australia.</strong> J. Neurol. Sci. 108: 7-17, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1352537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1352537</a>] [<a href="https://doi.org/10.1016/0022-510x(92)90181-j" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1352537">Sudoyo et al., 1992</a>; Vilkki et al. (<a href="#70" class="mim-tip-reference" title="Vilkki, J., Savontaus, M.-L., Nikoskelainen, E. K. <strong>Genetic heterogeneity in Leber hereditary optic neuroretinopathy revealed by mitochondrial DNA polymorphism.</strong> Am. J. Hum. Genet. 45: 206-211, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2757028/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2757028</a>]" pmid="2757028">1989</a>, <a href="#71" class="mim-tip-reference" title="Vilkki, J., Savontaus, M.-L., Nikoskelainen, E. K. <strong>Segregation of mitochondrial genomes in a heteroplasmic lineage with Leber hereditary optic neuroretinopathy.</strong> Am. J. Hum. Genet. 47: 95-100, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1971999/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1971999</a>]" pmid="1971999">1990</a>); <a href="#74" class="mim-tip-reference" title="Wallace, D. C., Singh, G., Lott, M. T., Hodge, J. A., Schurr, T. G., Lezza, A. M., Elsas, L. J., Nikoskelainen, E. K. <strong>Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy.</strong> Science 242: 1427-1430, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3201231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3201231</a>] [<a href="https://doi.org/10.1126/science.3201231" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3201231">Wallace et al., 1988</a>; <a href="#76" class="mim-tip-reference" title="Weiner, N. C., Newman, N. J., Lessell, S., Johns, D. R., Lott, M. T., Wallace, D. C. <strong>Atypical Leber's hereditary optic neuropathy with molecular confirmation.</strong> Arch. Neurol. 50: 470-473, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8489402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8489402</a>] [<a href="https://doi.org/10.1001/archneur.1993.00540050022009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8489402">Weiner et al., 1993</a>; <a href="#78" class="mim-tip-reference" title="Yoneda, M., Tsuji, S., Yamauchi, T., Inuzuka, T., Miyatake, T., Horai, S., Ozawa, T. <strong>Mitochondrial DNA mutation in family with Leber's hereditary optic neuropathy.</strong> Lancet 333: 1076-1077, 1989. Note: Originally Volume 1.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2566021/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2566021</a>] [<a href="https://doi.org/10.1016/s0140-6736(89)92470-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2566021">Yoneda et al., 1989</a>; <a href="#79" class="mim-tip-reference" title="Zhu, D., Economou, E. P., Antonarakis, S. E., Maumenee, I. H. <strong>Mitochondrial DNA mutation and heteroplasmy in type I Leber hereditary optic neuropathy.</strong> Am. J. Med. Genet. 42: 173-179, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1346348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1346348</a>] [<a href="https://doi.org/10.1002/ajmg.1320420208" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1346348">Zhu et al., 1992</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1895564+1959931+8489402+8489411+2566021+2222273+1353825+1770533+1977373+2575667+8240102+1866007+2346190+1734726+8449667+2346203+8448903+2039048+1346348+8457609+2757028+1532593+2286378+1352537+8250088+1959619+1770665+2566116+8240101+2390098+8240103+1763894+8474822+1417830+8101084+2817063+1900003+1971999+1937476+3201231" 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 37 Italian subjects with LHON, <a href="#69" class="mim-tip-reference" title="Torroni, A., Petrozzi, M., D'Urbano, L., Sellitto, D., Zeviani, M., Carrara, F., Carducci, C., Leuzzi, V., Carelli, V., Barboni, P., De Negri, A., Scozzari, R. <strong>Haplotype and phylogenetic analyses suggest that one European-specific mtDNA background plays a role in the expression of Leber hereditary optic neuropathy by increasing the penetrance of the primary mutations 11778 and 14484.</strong> Am. J. Hum. Genet. 60: 1107-1121, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9150158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9150158</a>]" pmid="9150158">Torroni et al. (1997)</a> found that 28 were 11778-positive, 7 were 3460-positive (<a href="/entry/516000#0001">516000.0001</a>) and 2 were 14484-positive (<a href="/entry/516006#0001">516006.0001</a>). High-resolution restriction endonuclease analysis was also performed in all subjects in order to define the phylogenetic relationships between mtDNA haplotypes and LHON mutations. Ninety-nine Italian controls were screened for mutations and haplotypes. The analysis showed that the putative secondary/intermediate LHON mutations 4216, 4917, 13708, 15257, and 15812 are ancient polymorphisms, are associated in specific combinations, and define 2 common Caucasoid-specific haplotype groupings, designated haplogroups J and T. On the contrary, the same analysis showed that the primary mutations 11778, 3460, and 14484 are recent and are due to multiple mutational events. However, phylogenetic analysis revealed a different evolutionary pattern for the 3 primary mutations. The 3460 mutations were distributed randomly along with phylogenetic trees, without any preferential association with the 9 haplotypes that characterize European populations, whereas the 11778 and 14484 mutations showed a strong preferential association with haplotype J. The findings suggested that one ancient combination of haplotype J with specific mutations increases the penetrance of the 2 primary mutations 11778 and 14484. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9150158" 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="#11" class="mim-tip-reference" title="Chinnery, P. F., Andrews, R. M., Turnbull, D. M., Howell, N. <strong>Leber hereditary optic neuropathy: does heteroplasmy influence the inheritance and expression of the G11778A mitochondrial DNA mutation?</strong> Am. J. Med. Genet. 98: 235-243, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11169561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11169561</a>] [<a href="https://doi.org/10.1002/1096-8628(20010122)98:3<235::aid-ajmg1086>3.0.co;2-o" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11169561">Chinnery et al. (2001)</a> analyzed 17 independent pedigrees that harbored the 11778G-A mutation. They made the following observations: (1) The frequency of blindness in males was related to the mutation load in the individual's blood. (2) Mothers with 80% or less mutant mtDNA in blood were less likely to have clinically affected sons than mothers with 100% mutant mtDNA in their blood. (3) Within individual lineages, changes in mutation load from one generation to the next were largely determined by random genetic drift. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11169561" 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="#77" class="mim-tip-reference" title="Wong, A., Cavelier, L., Collins-Schramm, H. E., Seldin, M. F., McGrogan, M., Savontaus, M.-L., Cortopassi, G. A. <strong>Differentiation-specific effects of LHON mutations introduced into neuronal NT2 cells.</strong> Hum. Molec. Genet. 11: 431-438, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11854175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11854175</a>] [<a href="https://doi.org/10.1093/hmg/11.4.431" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11854175">Wong et al. (2002)</a> created cybrids using a neuronal precursor cell line, NT2, containing mitochondria from patient lymphoblasts bearing the most common LHON mutation, 11778, and the most severe LHON mutation, 3460 (<a href="/entry/516000#0001">516000.0001</a>). The undifferentiated LHON-NT2 mutant cells were not significantly different from the parental cell control in terms of mtDNA/nDNA ratio, mitochondrial membrane potential, reactive oxygen species (ROS) production, or the ability to reduce the reagent Alamar blue. Differentiation of NT2s resulted in a neuronal morphology, a neuron-specific pattern of gene expression, and a 3-fold reduction in mtDNA/nDNA ratio in both mutant and control cells; however, the differentiation protocol yielded 30% less LHON cells than controls, indicating either a decreased proliferative potential or increased cell death of the LHON-NT2 cells. Differentiation of the cells to the neuronal form also resulted in significant increases in ROS production in the LHON-NT2 neurons versus controls, which was abolished by rotenone (a specific inhibitor of complex I). <a href="#77" class="mim-tip-reference" title="Wong, A., Cavelier, L., Collins-Schramm, H. E., Seldin, M. F., McGrogan, M., Savontaus, M.-L., Cortopassi, G. A. <strong>Differentiation-specific effects of LHON mutations introduced into neuronal NT2 cells.</strong> Hum. Molec. Genet. 11: 431-438, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11854175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11854175</a>] [<a href="https://doi.org/10.1093/hmg/11.4.431" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11854175">Wong et al. (2002)</a> inferred that the LHON genotype may require a differentiated neuronal environment in order to induce increased mitochondrial ROS, which may be the cause of the reduced NT2 yield. They hypothesized that the LHON degenerative phenotype may be the result of an increase in mitochondrial superoxide which is caused by the LHON mutations, possibly mediated through neuron-specific alterations in complex I structure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11854175" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Guy, J., Qi, X., Pallotti, F., Schon, E. A., Manfredi, G., Carelli, V., Martinuzzi, A., Hauswirth, W. W., Lewin, A. S. <strong>Rescue of a mitochondrial deficiency causing Leber hereditary optic neuropathy.</strong> Ann. Neurol. 52: 534-542, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12402249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12402249</a>] [<a href="https://doi.org/10.1002/ana.10354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12402249">Guy et al. (2002)</a> found that cybrid cells containing the 11778G-A mutation showed a 60% reduction in the rate of complex I-dependent ATP synthesis compared to wildtype cells. Using 'allotopic expression,' a technique in which a mitochondrial gene is expressed in the nucleus and the protein product is then imported back to the mitochondria, <a href="#22" class="mim-tip-reference" title="Guy, J., Qi, X., Pallotti, F., Schon, E. A., Manfredi, G., Carelli, V., Martinuzzi, A., Hauswirth, W. W., Lewin, A. S. <strong>Rescue of a mitochondrial deficiency causing Leber hereditary optic neuropathy.</strong> Ann. Neurol. 52: 534-542, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12402249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12402249</a>] [<a href="https://doi.org/10.1002/ana.10354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12402249">Guy et al. (2002)</a> transfected a fusion ND4 subunit gene into cybrids containing the 11778G-A mutation. Cybrid cell survival after 3 days was 3-fold greater for the allotopically transfected cells, and these cells showed a 3-fold increase in the rate of complex I-dependent ATP synthesis, to a level indistinguishable from that in normal cybrids. <a href="#22" class="mim-tip-reference" title="Guy, J., Qi, X., Pallotti, F., Schon, E. A., Manfredi, G., Carelli, V., Martinuzzi, A., Hauswirth, W. W., Lewin, A. S. <strong>Rescue of a mitochondrial deficiency causing Leber hereditary optic neuropathy.</strong> Ann. Neurol. 52: 534-542, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12402249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12402249</a>] [<a href="https://doi.org/10.1002/ana.10354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12402249">Guy et al. (2002)</a> suggested that this rescue of a severe oxidative phosphorylation deficiency held promise for development of gene therapy for mitochondrial disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12402249" 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="#45" class="mim-tip-reference" title="Mimaki, M., Ikota, A., Sato, A., Komaki, H., Akanuma, J., Nonaka, I., Goto, Y. <strong>A double mutation (G11778A and G12192A) in mitochondrial DNA associated with Leber's hereditary optic neuropathy and cardiomyopathy.</strong> J. Hum. Genet. 48: 47-50, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12560876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12560876</a>] [<a href="https://doi.org/10.1007/s100380300005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12560876">Mimaki et al. (2003)</a> reported a male patient with LHON and cardiomyopathy who had the 11778G-A mutation as well as a 12192G-A mutation in the MTTH gene (<a href="/entry/590040#0001">590040.0001</a>), which is a risk factor for cardiomyopathy. Because no case of LHON presenting with cardiomyopathy had previously been reported, the findings suggested that this was an instance of double pathogenic mtDNA mutations associated either synergistically or concomitantly with 2 different clinical manifestations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12560876" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of 87 index cases with LHON sequentially diagnosed in Italy, including an extremely large Brazilian family of Italian maternal ancestry, 67 subjects had the 11778/ND4 mutation. <a href="#8" class="mim-tip-reference" title="Carelli, V., Achilli, A., Valentino, M. L., Rengo, C., Semino, O., Pala, M., Olivieri, A., Mattiazzi, M., Pallotti, F., Carrara, F., Zeviani, M., Leuzzi, V., Carducci, C., Valle, G., Simionati, B., Mendieta, L., Salomao, S., Belfort, R., Jr., Sadun, A. A., Torroni, A. <strong>Haplogroup effects and recombination of mitochondrial DNA: novel clues from the analysis of Leber hereditary optic neuropathy pedigrees.</strong> Am. J. Hum. Genet. 78: 564-574, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16532388/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16532388</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16532388[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/10.1086/501236" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16532388">Carelli et al. (2006)</a> concluded that the large majority of LHON mutations were due to independent mutational events. In the 87 index cases, only 7 pairs and 3 triplets of identical haplotypes were observed. Assignment of the mutational events into haplogroups confirmed that J1 and J2 play a role in LHON expression but narrowed the association to the subclades J1c and J2b, thus suggesting that 2 specific combinations of amino acid changes in cytochrome b (<a href="/entry/516020">516020</a>) are the cause of the mtDNA background effect and that this may occur at the level of the supercomplex formed by respiratory chain complexes I and III. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16532388" 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="#57" class="mim-tip-reference" title="Phasukkijwatana, N., Chuenkongkaew, W. L., Suphavilai, R., Suktitipat, B., Pingsuthiwong, S., Ruangvaravate, N., Atchaneeyasakul, L., Warrasak, S., Poonyathalang, A., Sura, T., Lertrit, P. <strong>The unique characteristics of Thai Leber hereditary optic neuropathy: analysis of 30 G11778A pedigrees.</strong> J. Hum. Genet. 51: 298-304, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16477364/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16477364</a>] [<a href="https://doi.org/10.1007/s10038-006-0361-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16477364">Phasukkijwatana et al. (2006)</a> examined 30 unrelated pedigrees of Thai or Chinese origin with LHON and the 11778G-A mutation. Compared to Caucasian and Japanese populations with the same mutation, the pedigrees in the study showed a lower male-to-female ratio (2.6:1) of affected persons and a higher prevalence of blood heteroplasmy (37% of the pedigrees contained at least 1 heteroplasmic 11778G-A individual). The estimated overall penetrance was 37% for males and 13% for females. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16477364" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a 3-generation Chinese family that exhibited high penetrance and expressivity of visual impairment due to LHON, <a href="#60" class="mim-tip-reference" title="Qu, J., Li, R., Zhou, X., Tong, Y., Lu, F., Qian, Y., Hu, Y., Mo, J. Q., West, C. E., Guan, M.-X. <strong>The novel A4435G mutation in the mitochondrial tRNA-Met may modulate the phenotypic expression of the LHON-associated ND4 G11778A mutation.</strong> Invest. Ophthal. Vis. Sci. 47: 475-483, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16431939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16431939</a>] [<a href="https://doi.org/10.1167/iovs.05-0665" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16431939">Qu et al. (2006)</a> identified the homoplasmic 11778G-A mutation and 35 other variants in the MTND4 gene belonging to the Asian haplogroup D5. One of the other variants, a novel homoplasmic 4435A-G mutation, which is localized at the 3-prime end adjacent to the anticodon, at conventional position 37 (A37), was absent in 164 Chinese controls. A37 in MTND4 is extraordinarily conserved from bacteria to human mitochondria. The modified A37 was shown to contribute to the high fidelity of codon recognition and to the structural formation and stabilization of functional tRNAs. A significant reduction of the steady state levels in tRNA-Met was observed in cells carrying both the 4435A-G and 11778G-A mutations but not in cells carrying only the 11778G-A mutation. Thus, a failure in mitochondrial tRNA metabolism, caused by the 4435A-G mutation, might worsen the mitochondrial dysfunction associated with the primary 11778G-A mutation. <a href="#60" class="mim-tip-reference" title="Qu, J., Li, R., Zhou, X., Tong, Y., Lu, F., Qian, Y., Hu, Y., Mo, J. Q., West, C. E., Guan, M.-X. <strong>The novel A4435G mutation in the mitochondrial tRNA-Met may modulate the phenotypic expression of the LHON-associated ND4 G11778A mutation.</strong> Invest. Ophthal. Vis. Sci. 47: 475-483, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16431939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16431939</a>] [<a href="https://doi.org/10.1167/iovs.05-0665" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16431939">Qu et al. (2006)</a> concluded that the novel 4435A-G mutation had a potential modifier role in increasing the penetrance and expressivity of the primary LHON-associated G11778A mutation in the Chinese family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16431939" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To create an animal model of LHON, <a href="#19" class="mim-tip-reference" title="Ellouze, S., Augustin, S., Bouaita, A., Bonnet, C., Simonutti, M., Forster, V., Picaud, S., Sahel, J.-A., Corral-Debrinski, M. <strong>Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction.</strong> Am. J. Hum. Genet. 83: 373-387, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18771762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18771762</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18771762[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.08.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18771762">Ellouze et al. (2008)</a> introduced the human ND4 gene harboring the 11778G-A mutation, responsible for 60% of LHON cases, into rat eyes by in vivo electroporation. The treatment induced the degeneration of retinal ganglion cells, which were 40% less abundant in treated eyes than in control eyes. This deleterious effect was also confirmed in primary cell culture, in which both RGC survival and neurite outgrowth were compromised. Importantly, RGC loss was clearly associated with a decline in visual performance. A subsequent electroporation with wildtype ND4 prevented both RGC loss and the impairment of visual function. <a href="#19" class="mim-tip-reference" title="Ellouze, S., Augustin, S., Bouaita, A., Bonnet, C., Simonutti, M., Forster, V., Picaud, S., Sahel, J.-A., Corral-Debrinski, M. <strong>Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction.</strong> Am. J. Hum. Genet. 83: 373-387, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18771762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18771762</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18771762[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.08.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18771762">Ellouze et al. (2008)</a> concluded that their data provided the proof of principle that optimized allotopic expression can be an effective treatment for LHON, and that they opened the way to clinical studies of other devastating mitochondrial disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18771762" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By studying the penetrance of LHON in 1,859 individuals from 182 Chinese families (including 1 from Cambodia) with the MTND4 11778G-A mutation, <a href="#30" class="mim-tip-reference" title="Ji, Y., Zhang, A.-M., Jia, X., Zhang, Y.-P., Xiao, X., Li, S., Guo, X., Bandelt, H.-J., Zhang, Q., Yao, Y.-G. <strong>Mitochondrial DNA haplogroups M7b1-prime-2 and M8a affect clinical expression of Leber hereditary optic neuropathy in Chinese families with the m.11778G-A mutation.</strong> Am. J. Hum. Genet. 83: 760-768, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19026397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19026397</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19026397[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.11.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19026397">Ji et al. (2008)</a> found that mitochondrial haplogroup M7b1-prime-2 was associated with increased risk of visual loss, whereas the M8a haplogroup was associated with decreased risk of visual loss. Further sequence analysis suggested that the M7b1-prime-2 effect was due to variation in the MTND5 (<a href="/entry/516005">516005</a>) gene, and that the M8a effect was due to variation in the MTATP6 gene (<a href="/entry/516060">516060</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19026397" 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>See LOAM (<a href="/entry/308905">308905</a>) for discussion of a form of LHON with increased penetrance and earlier age of onset resulting from additional mutation in the PRICKLE3 gene (<a href="/entry/300111#0001">300111.0001</a>) acting as a modifier of disease expression.</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">rs199476113 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476113;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=rs199476113" 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=rs199476113" 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 moderately conserved threonine at amino acid 109 to an alanine (T109A). It was found in a 19-year-old female with a history of intermittent migraines, sensorineural hearing loss, bilateral cataracts, grand mal seizures, stroke-like episodes, lactic acidosis, and ragged-red muscle fibers (MELAS syndrome; <a href="/entry/540000">540000</a>). An older brother and the mother had milder symptoms (<a href="#16" class="mim-tip-reference" title="Danks, R. A., Dorevitch, M., Cummins, J. T., Byrne, E. <strong>Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS): adolescent onset with severe cerebral edema.</strong> Aust. New Zeal. J. Med. 18: 69-72, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3395302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3395302</a>] [<a href="https://doi.org/10.1111/j.1445-5994.1988.tb02245.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3395302">Danks et al., 1988</a>; <a href="#39" class="mim-tip-reference" title="Lertrit, P., Noer, A. S., Jean-Francois, M. J., Kapsa, R., Dennett, X., Thyagarajan, D., Lethlean, K., Byrne, E., Marzuki, S. <strong>A new disease-related mutation for mitochondrial encephalopathy lactic acidosis and strokelike episodes (MELAS) syndrome affects the ND4 subunit of the respiratory complex I.</strong> Am. J. Hum. Genet. 51: 457-468, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1323207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1323207</a>]" pmid="1323207">Lertrit et al., 1992</a>). Later this mutation was found in 14% of Asians, which suggests that it may be a polymorphism (<a href="#62" class="mim-tip-reference" title="Sakuta, R., Goto, Y., Nonake, I., Horai, S. <strong>An A-to-G transition at nucleotide pair 11084 in the ND4 gene may be an mtDNA polymorphism. (Letter)</strong> Am. J. Hum. Genet. 53: 964-965, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8213827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8213827</a>]" pmid="8213827">Sakuta et al., 1993</a>) and not related to the MELAS (<a href="/entry/540000">540000</a>)-like symptoms of this family. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8213827+3395302+1323207" 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">rs200873900 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs200873900;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=rs200873900" 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=rs200873900" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>Hereditary spastic dystonia and LHON (see <a href="/entry/535000">535000</a> and <a href="/entry/500001">500001</a>), manifested either separately or in combination, had occurred among 24 individuals over 7 generations of a large Dutch family (<a href="#6" class="mim-tip-reference" title="Bruyn, G. W., Bots, G. T. A. M., Went, L. N., Klinkhamer, P. J. J. M. <strong>Hereditary spastic dystonia with Leber's hereditary optic neuropathy: neuropathological findings.</strong> J. Neurol. Sci. 113: 55-61, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1469456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1469456</a>] [<a href="https://doi.org/10.1016/0022-510x(92)90265-m" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1469456">Bruyn et al., 1992</a>). Both the dystonia and LHON showed strict maternal inheritance. Of the maternal relatives, 12 had optic atrophy only, 4 exhibited exclusively the neurologic disorder (1 with unilateral involvement), and 8 presented with optic atrophy and the neurologic disorder; 1 of these 8 had a unilateral neurologic deficit. <a href="#17" 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 11696 in the ND4 gene that resulted in substitution of an isoleucine for valine at amino acid position 312. The second mutation, a homoplasmic T-to-A transition at nucleotide position 14596 in the ND6 gene (<a href="/entry/516006#0003">516006.0003</a>), resulted in the substitution of a methionine for the isoleucine at amino acid residue 26. Biochemical analysis of a muscle biopsy revealed severe complex I deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8644732+1469456" 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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MTND4, 11777C-A
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28384199 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28384199;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=rs28384199" 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=rs28384199" 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=RCV000010357 OR RCV000144013 OR RCV000854746 OR RCV002260594" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010357, RCV000144013, RCV000854746, RCV002260594" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010357...</a>
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<p>In a 67-year-old man with cognitive deficits, status epilepticus, hemiparesis, and severe lactic acidosis, <a href="#18" class="mim-tip-reference" title="Deschauer, M., Bamberg, C., Claus, D., Zierz, S., Turnbull, D. M., Taylor, R. W. <strong>Late-onset encephalopathy associated with a C11777A mutation of mitochondrial DNA.</strong> Neurology 60: 1357-1359, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12707444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12707444</a>] [<a href="https://doi.org/10.1212/01.wnl.0000055869.99975.4b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12707444">Deschauer et al. (2003)</a> identified a heteroplasmic 11777C-A mutation in the MTND4 gene. Respiratory chain analysis of skeletal muscle showed a defect in the activity of complex I (40% of control) (<a href="/entry/252010">252010</a>). The authors noted that the patient had stroke-like symptoms similar to those observed in the MELAS syndrome (<a href="/entry/540000">540000</a>) but with later onset. The mutation occurred in the same codon as the 11778G-A mutation (<a href="#0001">516003.0001</a>) that causes Leber hereditary optic neuropathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12707444" 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="seeAlso" class="mim-anchor"></a>
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<h4 href="#mimSeeAlsoFold" id="mimSeeAlsoToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-font">
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<span id="mimSeeAlsoToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>See Also:</strong>
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<a href="#Johns1992" class="mim-tip-reference" title="Johns, D. R., Smith, K. H., Miller, N. R. <strong>Leber's Hereditary Optic Neuropathy. Clinical manifestations of the 3460 mutation.</strong> Arch. Ophthal. 110: 1577-1581, 1992.">Johns et al. (1992)</a>; <a href="#Mashima1993" class="mim-tip-reference" title="Mashima, Y., Hiida, Y., Oguchi, Y., Kudoh, J., Shimizu, N. <strong>High frequency of mutations at position 11778 in mitochondrial ND4 gene in Japanese families with Leber's hereditary optic neuropathy.</strong> Hum. Genet. 92: 101-102, 1993.">Mashima et al. (1993)</a>; <a href="#Montoya1981" 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.">Montoya et al. (1981)</a>; <a href="#Nakamura1992" class="mim-tip-reference" title="Nakamura, M., Ara, F., Yamada, M., Hotta, Y., Hayakawa, M., Fujiki, K., Kanai, A., Sakai, J., Inoue, M., Yamamoto, M., Fujiwara, Y., Umoto, A., Miyazaki, S., Shimo-Oku, M., Furuyama, J.-I., Nakajima, A., Imachi, J. <strong>High frequency of mitochondrial ND4 gene mutation in Japanese pedigrees with Leber hereditary optic neuropathy.</strong> Jpn. J. Ophthal. 36: 56-61, 1992.">Nakamura et al. (1992)</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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[<a href="https://doi.org/10.1038/290457a0" target="_blank">Full Text</a>]
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<a id="Arizmendi1992" class="mim-anchor"></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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<a id="Attardi1986" class="mim-anchor"></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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[<a href="https://doi.org/10.1101/sqb.1986.051.01.013" target="_blank">Full Text</a>]
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<a id="Attardi1982" class="mim-anchor"></a>
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<p class="mim-text-font">
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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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<a id="Bolhuis1990" class="mim-anchor"></a>
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Bolhuis, P. A., Bleeker-Wagemakers, E. M., Ponne, N. J., Van Schooneveld, M. J., Westerveld, A., Van den Bogert, C., Tabak, H. F.
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<strong>Rapid shift in genotype of human mitochondrial DNA in a family with Leber's hereditary optic neuropathy.</strong>
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Biochem. Biophys. Res. Commun. 170: 994-997, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2390098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2390098</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2390098" 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/10.1016/0006-291x(90)90490-e" target="_blank">Full Text</a>]
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<a id="Bruyn1992" class="mim-anchor"></a>
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Bruyn, G. W., Bots, G. T. A. M., Went, L. N., Klinkhamer, P. J. J. M.
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<strong>Hereditary spastic dystonia with Leber's hereditary optic neuropathy: neuropathological findings.</strong>
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J. Neurol. Sci. 113: 55-61, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1469456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1469456</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1469456" 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/10.1016/0022-510x(92)90265-m" target="_blank">Full Text</a>]
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<a id="Carducci1991" class="mim-anchor"></a>
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Carducci, C., Leuzzi, V., Scuderi, M., De Negri, A. M., Gabrieli, C. B., Antonozzi, I., Pontecorvi, A.
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<strong>Mitochondrial DNA mutation in an Italian family with Leber hereditary optic neuropathy.</strong>
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Hum. Genet. 87: 725-727, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1937476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1937476</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1937476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/BF00201733" target="_blank">Full Text</a>]
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<a id="Carelli2006" class="mim-anchor"></a>
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Carelli, V., Achilli, A., Valentino, M. L., Rengo, C., Semino, O., Pala, M., Olivieri, A., Mattiazzi, M., Pallotti, F., Carrara, F., Zeviani, M., Leuzzi, V., Carducci, C., Valle, G., Simionati, B., Mendieta, L., Salomao, S., Belfort, R., Jr., Sadun, A. A., Torroni, A.
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<strong>Haplogroup effects and recombination of mitochondrial DNA: novel clues from the analysis of Leber hereditary optic neuropathy pedigrees.</strong>
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Am. J. Hum. Genet. 78: 564-574, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16532388/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16532388</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16532388[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16532388" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/501236" target="_blank">Full Text</a>]
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Case, J. T., Wallace, D. C.
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<strong>Maternal inheritance of mitochondrial DNA polymorphisms in cultured human fibroblasts.</strong>
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Somat. Cell Genet. 7: 103-108, 1981.
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[<a href="https://doi.org/10.1007/BF01544751" target="_blank">Full Text</a>]
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<strong>Intrafamilial variation in Leber hereditary optic neuropathy revealed by direct mutation analysis.</strong>
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Clin. Genet. 43: 69-72, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8448903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8448903</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8448903" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.1993.tb04429.x" target="_blank">Full Text</a>]
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Chinnery, P. F., Andrews, R. M., Turnbull, D. M., Howell, N.
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<strong>Leber hereditary optic neuropathy: does heteroplasmy influence the inheritance and expression of the G11778A mitochondrial DNA mutation?</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11169561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11169561</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11169561" 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/10.1002/1096-8628(20010122)98:3<235::aid-ajmg1086>3.0.co;2-o" target="_blank">Full Text</a>]
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Chomyn, A., Cleeter, W. J., Ragan, C. I., Riley, M., Doolittle, R. F., Attardi, G.
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<strong>URF6, last unidentified reading frame of human mtDNA, codes for an NADH dehydrogenase subunit.</strong>
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Science 234: 614-618, 1986.
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[<a href="https://doi.org/10.1016/j.ajhg.2008.11.002" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0006-291x(91)91567-v" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0006-291x(92)90479-5" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archopht.1993.01090110057023" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archopht.1992.01080230077025" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archopht.1990.01070120053027" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/nar/24.1.177" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00204937" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.410300511" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0002-9394(14)72429-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0014-5793(91)80886-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0002-9394(14)73485-3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00216156" target="_blank">Full Text</a>]
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Stone, E. M., Coppinger, J. M., Kardon, R. H., Donelson, J.
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<strong>Mae III positively detects the mitochondrial mutation associated with type I Leber's hereditary optic neuropathy.</strong>
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Arch. Ophthal. 108: 1417-1420, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1977373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1977373</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1977373" 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/archopht.1990.01070120065030" target="_blank">Full Text</a>]
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<a id="Stone1992" class="mim-anchor"></a>
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Stone, E. M., Newman, N. J., Miller, N. R., Johns, D. R., Lott, M. T., Wallace, D. C.
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<strong>Visual recovery in patients with Leber's hereditary optic neuropathy and the 11778 mutation.</strong>
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J. Clin. Neuroophthalmol. 12: 10-14, 1992.
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<a id="Sudoyo1992" class="mim-anchor"></a>
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<p class="mim-text-font">
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Sudoyo, H., Marzuki, S., Mastaglia, F., Carroll, W.
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<strong>Molecular genetics of Leber's hereditary optic neuropathy: study of a six-generation family from Western Australia.</strong>
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J. Neurol. Sci. 108: 7-17, 1992.
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[<a href="https://doi.org/10.1016/0022-510x(92)90181-j" target="_blank">Full Text</a>]
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Torroni, A., Petrozzi, M., D'Urbano, L., Sellitto, D., Zeviani, M., Carrara, F., Carducci, C., Leuzzi, V., Carelli, V., Barboni, P., De Negri, A., Scozzari, R.
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<strong>Haplotype and phylogenetic analyses suggest that one European-specific mtDNA background plays a role in the expression of Leber hereditary optic neuropathy by increasing the penetrance of the primary mutations 11778 and 14484.</strong>
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Am. J. Hum. Genet. 60: 1107-1121, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9150158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9150158</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9150158" 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="Vilkki1989" class="mim-anchor"></a>
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<p class="mim-text-font">
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Vilkki, J., Savontaus, M.-L., Nikoskelainen, E. K.
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<strong>Genetic heterogeneity in Leber hereditary optic neuroretinopathy revealed by mitochondrial DNA polymorphism.</strong>
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Am. J. Hum. Genet. 45: 206-211, 1989.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2757028/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2757028</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2757028" 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="Vilkki1990" class="mim-anchor"></a>
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<p class="mim-text-font">
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Vilkki, J., Savontaus, M.-L., Nikoskelainen, E. K.
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<strong>Segregation of mitochondrial genomes in a heteroplasmic lineage with Leber hereditary optic neuroretinopathy.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1971999/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1971999</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1971999" 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="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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[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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<a id="Wallace1988" class="mim-anchor"></a>
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Wallace, D. C., Singh, G., Lott, M. T., Hodge, J. A., Schurr, T. G., Lezza, A. M., Elsas, L. J., Nikoskelainen, E. K.
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<strong>Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy.</strong>
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Science 242: 1427-1430, 1988.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3201231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3201231</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3201231" 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.3201231" target="_blank">Full Text</a>]
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<a id="Wallace1986" class="mim-anchor"></a>
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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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Weiner, N. C., Newman, N. J., Lessell, S., Johns, D. R., Lott, M. T., Wallace, D. C.
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<strong>Atypical Leber's hereditary optic neuropathy with molecular confirmation.</strong>
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Arch. Neurol. 50: 470-473, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8489402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8489402</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8489402" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1001/archneur.1993.00540050022009" target="_blank">Full Text</a>]
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Wong, A., Cavelier, L., Collins-Schramm, H. E., Seldin, M. F., McGrogan, M., Savontaus, M.-L., Cortopassi, G. A.
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<strong>Differentiation-specific effects of LHON mutations introduced into neuronal NT2 cells.</strong>
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Hum. Molec. Genet. 11: 431-438, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11854175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11854175</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11854175" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/11.4.431" target="_blank">Full Text</a>]
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Yoneda, M., Tsuji, S., Yamauchi, T., Inuzuka, T., Miyatake, T., Horai, S., Ozawa, T.
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<strong>Mitochondrial DNA mutation in family with Leber's hereditary optic neuropathy.</strong>
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Lancet 333: 1076-1077, 1989. Note: Originally Volume 1.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2566021/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2566021</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2566021" 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/s0140-6736(89)92470-7" target="_blank">Full Text</a>]
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Zhu, D., Economou, E. P., Antonarakis, S. E., Maumenee, I. H.
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<strong>Mitochondrial DNA mutation and heteroplasmy in type I Leber hereditary optic neuropathy.</strong>
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Am. J. Med. Genet. 42: 173-179, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1346348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1346348</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1346348" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320420208" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 1/21/2009
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Ada Hamosh - updated : 11/5/2008<br>Jane Kelly - updated : 11/14/2006<br>Cassandra L. Kniffin - updated : 5/24/2006<br>Victor A. McKusick - updated : 3/15/2006<br>Cassandra L. Kniffin - updated : 6/23/2003<br>Victor A. McKusick - updated : 2/11/2003<br>Cassandra L. Kniffin - updated : 1/2/2003<br>George E. Tiller - updated : 9/27/2002<br>Victor A. McKusick - updated : 2/20/2001<br>Victor A. McKusick - updated : 6/16/1997<br>Douglas C. Wallace - updated : 4/6/1994
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Victor A. McKusick : 3/2/1993
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alopez : 08/11/2023<br>alopez : 01/14/2021<br>alopez : 09/23/2016<br>carol : 07/08/2016<br>terry : 5/24/2011<br>terry : 11/3/2010<br>carol : 1/19/2010<br>terry : 6/5/2009<br>carol : 1/22/2009<br>ckniffin : 1/21/2009<br>alopez : 12/1/2008<br>alopez : 12/1/2008<br>terry : 11/5/2008<br>terry : 8/26/2008<br>carol : 11/14/2006<br>wwang : 5/31/2006<br>ckniffin : 5/24/2006<br>alopez : 3/21/2006<br>terry : 3/15/2006<br>carol : 9/21/2005<br>ckniffin : 8/29/2005<br>carol : 7/9/2003<br>ckniffin : 6/23/2003<br>carol : 2/21/2003<br>carol : 2/21/2003<br>tkritzer : 2/13/2003<br>terry : 2/11/2003<br>tkritzer : 1/16/2003<br>tkritzer : 1/8/2003<br>ckniffin : 1/2/2003<br>cwells : 9/27/2002<br>ckniffin : 8/27/2002<br>mcapotos : 2/23/2001<br>mcapotos : 2/21/2001<br>mcapotos : 2/20/2001<br>mcapotos : 2/20/2001<br>alopez : 9/8/2000<br>alopez : 3/14/2000<br>dholmes : 4/17/1998<br>terry : 12/11/1997<br>terry : 7/10/1997<br>terry : 7/10/1997<br>terry : 6/16/1997<br>terry : 1/21/1997<br>terry : 4/19/1996<br>terry : 4/15/1996<br>mark : 4/1/1996<br>mark : 3/30/1996<br>terry : 3/12/1996<br>mimman : 2/8/1996<br>mark : 6/19/1995<br>pfoster : 11/28/1994<br>davew : 7/5/1994<br>jason : 6/27/1994<br>mimadm : 5/13/1994
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<span class="mim-font">
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<strong>*</strong> 516003
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<h3>
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COMPLEX I, SUBUNIT ND4; MTND4
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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NADH-UBIQUINONE OXIDOREDUCTASE, SUBUNIT ND4<br />
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NADH DEHYDROGENASE, SUBUNIT 4
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: MT-ND4</em></strong>
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<strong>SNOMEDCT:</strong> 237988006, 39925003, 58610003;
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<strong>ICD10CM:</strong> E88.41, H47.22;
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>Subunit 4 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 out across the mitochondrial inner membrane. Complex I is more fully described in 516000. MTND4 is probably a component of the hydrophobic protein fragment (Ragan, 1987). </p>
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<strong>Mapping</strong>
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<p>MTND4 is encoded by the guanine-rich heavy (H) strand of the mtDNA and located between nucleotide pair (nps) 10760 and 12137 (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 MTND4 gene encompasses 1377 nps of continuous coding sequence. It is part of a bicistronic mRNA, occupying the 3-prime end while its companion gene, MTND4L, occupies the 5-prime end. The MTND4 protein coding sequence begins 291 np from the 5-prime end of the mRNA, with its seven 5-prime nucleotides overlapping with the last 2 codons and termination codon of MTND4L. The MTND4 open reading frame is continuous without introns and ends with the U of the UAA termination codon (Anderson et al., 1981; Wallace et al., 1994; Ojala et al., 1981). The bicistronic MTND4L + MTND4 mRNA is transcribed as a part of the polycistronic H-strand transcript, flanked by tRNA Arg at the 5-prime end and tRNA His at the 3-prime end. These tRNAs are cleaved from the transcript freeing transcript 7, the MTND4L + MTND4 mRNA. The mRNA is then polyadenylated completing the MTND4 termination codon (Anderson et al., 1981; Ojala et al., 1981; Attardi et al., 1982; Wallace et al., 1994). </p>
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<strong>Gene Function</strong>
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<p>The predicted polypeptide molecular weight is 51.4 kD (Anderson et al., 1981). However, the apparent molecular weight upon SDS-polyacrylamide gel electrophoresis (PAGE) using Tris-glycine buffer is 36.5 kD (Wallace et al., 1986; Oliver et al., 1984) whereas with urea-phosphate buffer it is 36 to 39 kD (Chomyn et al., 1985). </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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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: +11100, +11321, +11350, -11362, +11425, +11469, -11576, +11806, +11892; Ava II: -11577; Dde I: +11074, +11146, +11793; Hae II: +11001, +11968; Hae III: +11092, +11313, +11329/11690, +11390/13633; Hha I: +11002, -11691, +11969; HincII: +12026; HinfI: +10806, -10830, -10971, -11403, +12008; Hpa I: +12026; Mbo I: +10934, -11922, +11431, +11439; Msp I: +11161, -11688, -12123; Rsa I: +11063, -11447, -11546, +11900, +11974; Taq I: +10893, +11924 (Wallace et al., 1994). </p><p>The major MTND4 allele is a mutation at np 11778 (MTND4*LHON11778A; 516003.0001) which causes Leber hereditary optic neuropathy (LHON; 535000) (Wallace et al., 1988). Pilz et al. (1994) observed the Wolfram syndrome (598500) in a man with this mutation. A combination with another undetected mutation in the mitochondrial genome or with a mutation in the nuclear genome or coincidental occurrence with the autosomal form of the disorder (222300) in heterozygous or homozygous form may account for the finding. </p><p>Kogelnik et al. (1996) described a comprehensive database, MITOMAP, for human mitochondrial DNA. MITOMAP uses the mtDNA sequence information on mitochondrial genome structure and function, pathogenic mutations and their clinical characteristics, population-associated variation, and gene-gene interactions. MITOMAP not only provides a valuable reference for the mitochondrial biologist but also provides a model for development of information storage and retrieval systems for other components of the human genome. </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>4 Selected Examples):</strong>
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</h4>
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<h4>
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<span class="mim-font">
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<strong>.0001 LEBER OPTIC ATROPHY</strong>
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</span>
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</h4>
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MTND4, LHON11778A
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SNP: rs199476112,
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ClinVar: RCV000010354, RCV000224219, RCV002260593, RCV002285007, RCV002288481, RCV004814875, RCV004814876
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<p>The allele changes the highly conserved arginine at amino acid 340 to a histidine (R340H). This allele accounts for over 50% of Leber hereditary optic neuropathy (LHON; 535000) cases among Caucasians and over 90% of the cases in Asians. The mutation has not been observed in random population controls, may be either homoplasmic or heteroplasmic within families, and has been shown to have arisen multiple times on different mtDNA haplotypes in association with the disease (Wallace et al., 1988; Singh et al., 1989). In families harboring this mutation, approximately 33 to 60% of the maternal relatives are affected and of these, about 80% are males. Visual recovery is seen in only 4% of cases (see LHON Table, MIM11 foreword section) (Bolhuis et al., 1990; Carducci et al., 1991; Cavelier et al., 1993; Cortelli et al., 1991; Cullom et al., 1993; Erickson and Castora, 1993; Hiida et al. (1991, 1992); Holt et al., 1989; Hotta et al., 1989; Howell et al., 1992; Huoponen et al., 1990; Isashiki and Nakagawa, 1991; Johns, 1990; Johns and Berman, 1991; Johns et al. (1992, 1993); Kormann et al., 1991; Larsson et al., 1991; Lott et al., 1990; Majander et al., 1991; Mashima et al. (1992, 1993); Moorman et al., 1993; Nakamura et al., 1993; Newman, 1993; Newman et al., 1991; Newman and Wallace, 1990; Norby, 1993; Poulton et al., 1991; Singh et al., 1989; Smith et al., 1993; Stone et al. (1990, 1992); Sudoyo et al., 1992; Vilkki et al. (1989, 1990); Wallace et al., 1988; Weiner et al., 1993; Yoneda et al., 1989; Zhu et al., 1992). </p><p>In 37 Italian subjects with LHON, Torroni et al. (1997) found that 28 were 11778-positive, 7 were 3460-positive (516000.0001) and 2 were 14484-positive (516006.0001). High-resolution restriction endonuclease analysis was also performed in all subjects in order to define the phylogenetic relationships between mtDNA haplotypes and LHON mutations. Ninety-nine Italian controls were screened for mutations and haplotypes. The analysis showed that the putative secondary/intermediate LHON mutations 4216, 4917, 13708, 15257, and 15812 are ancient polymorphisms, are associated in specific combinations, and define 2 common Caucasoid-specific haplotype groupings, designated haplogroups J and T. On the contrary, the same analysis showed that the primary mutations 11778, 3460, and 14484 are recent and are due to multiple mutational events. However, phylogenetic analysis revealed a different evolutionary pattern for the 3 primary mutations. The 3460 mutations were distributed randomly along with phylogenetic trees, without any preferential association with the 9 haplotypes that characterize European populations, whereas the 11778 and 14484 mutations showed a strong preferential association with haplotype J. The findings suggested that one ancient combination of haplotype J with specific mutations increases the penetrance of the 2 primary mutations 11778 and 14484. </p><p>Chinnery et al. (2001) analyzed 17 independent pedigrees that harbored the 11778G-A mutation. They made the following observations: (1) The frequency of blindness in males was related to the mutation load in the individual's blood. (2) Mothers with 80% or less mutant mtDNA in blood were less likely to have clinically affected sons than mothers with 100% mutant mtDNA in their blood. (3) Within individual lineages, changes in mutation load from one generation to the next were largely determined by random genetic drift. </p><p>Wong et al. (2002) created cybrids using a neuronal precursor cell line, NT2, containing mitochondria from patient lymphoblasts bearing the most common LHON mutation, 11778, and the most severe LHON mutation, 3460 (516000.0001). The undifferentiated LHON-NT2 mutant cells were not significantly different from the parental cell control in terms of mtDNA/nDNA ratio, mitochondrial membrane potential, reactive oxygen species (ROS) production, or the ability to reduce the reagent Alamar blue. Differentiation of NT2s resulted in a neuronal morphology, a neuron-specific pattern of gene expression, and a 3-fold reduction in mtDNA/nDNA ratio in both mutant and control cells; however, the differentiation protocol yielded 30% less LHON cells than controls, indicating either a decreased proliferative potential or increased cell death of the LHON-NT2 cells. Differentiation of the cells to the neuronal form also resulted in significant increases in ROS production in the LHON-NT2 neurons versus controls, which was abolished by rotenone (a specific inhibitor of complex I). Wong et al. (2002) inferred that the LHON genotype may require a differentiated neuronal environment in order to induce increased mitochondrial ROS, which may be the cause of the reduced NT2 yield. They hypothesized that the LHON degenerative phenotype may be the result of an increase in mitochondrial superoxide which is caused by the LHON mutations, possibly mediated through neuron-specific alterations in complex I structure. </p><p>Guy et al. (2002) found that cybrid cells containing the 11778G-A mutation showed a 60% reduction in the rate of complex I-dependent ATP synthesis compared to wildtype cells. Using 'allotopic expression,' a technique in which a mitochondrial gene is expressed in the nucleus and the protein product is then imported back to the mitochondria, Guy et al. (2002) transfected a fusion ND4 subunit gene into cybrids containing the 11778G-A mutation. Cybrid cell survival after 3 days was 3-fold greater for the allotopically transfected cells, and these cells showed a 3-fold increase in the rate of complex I-dependent ATP synthesis, to a level indistinguishable from that in normal cybrids. Guy et al. (2002) suggested that this rescue of a severe oxidative phosphorylation deficiency held promise for development of gene therapy for mitochondrial disorders. </p><p>Mimaki et al. (2003) reported a male patient with LHON and cardiomyopathy who had the 11778G-A mutation as well as a 12192G-A mutation in the MTTH gene (590040.0001), which is a risk factor for cardiomyopathy. Because no case of LHON presenting with cardiomyopathy had previously been reported, the findings suggested that this was an instance of double pathogenic mtDNA mutations associated either synergistically or concomitantly with 2 different clinical manifestations. </p><p>In a study of 87 index cases with LHON sequentially diagnosed in Italy, including an extremely large Brazilian family of Italian maternal ancestry, 67 subjects had the 11778/ND4 mutation. Carelli et al. (2006) concluded that the large majority of LHON mutations were due to independent mutational events. In the 87 index cases, only 7 pairs and 3 triplets of identical haplotypes were observed. Assignment of the mutational events into haplogroups confirmed that J1 and J2 play a role in LHON expression but narrowed the association to the subclades J1c and J2b, thus suggesting that 2 specific combinations of amino acid changes in cytochrome b (516020) are the cause of the mtDNA background effect and that this may occur at the level of the supercomplex formed by respiratory chain complexes I and III. </p><p>Phasukkijwatana et al. (2006) examined 30 unrelated pedigrees of Thai or Chinese origin with LHON and the 11778G-A mutation. Compared to Caucasian and Japanese populations with the same mutation, the pedigrees in the study showed a lower male-to-female ratio (2.6:1) of affected persons and a higher prevalence of blood heteroplasmy (37% of the pedigrees contained at least 1 heteroplasmic 11778G-A individual). The estimated overall penetrance was 37% for males and 13% for females. </p><p>In affected members of a 3-generation Chinese family that exhibited high penetrance and expressivity of visual impairment due to LHON, Qu et al. (2006) identified the homoplasmic 11778G-A mutation and 35 other variants in the MTND4 gene belonging to the Asian haplogroup D5. One of the other variants, a novel homoplasmic 4435A-G mutation, which is localized at the 3-prime end adjacent to the anticodon, at conventional position 37 (A37), was absent in 164 Chinese controls. A37 in MTND4 is extraordinarily conserved from bacteria to human mitochondria. The modified A37 was shown to contribute to the high fidelity of codon recognition and to the structural formation and stabilization of functional tRNAs. A significant reduction of the steady state levels in tRNA-Met was observed in cells carrying both the 4435A-G and 11778G-A mutations but not in cells carrying only the 11778G-A mutation. Thus, a failure in mitochondrial tRNA metabolism, caused by the 4435A-G mutation, might worsen the mitochondrial dysfunction associated with the primary 11778G-A mutation. Qu et al. (2006) concluded that the novel 4435A-G mutation had a potential modifier role in increasing the penetrance and expressivity of the primary LHON-associated G11778A mutation in the Chinese family. </p><p>To create an animal model of LHON, Ellouze et al. (2008) introduced the human ND4 gene harboring the 11778G-A mutation, responsible for 60% of LHON cases, into rat eyes by in vivo electroporation. The treatment induced the degeneration of retinal ganglion cells, which were 40% less abundant in treated eyes than in control eyes. This deleterious effect was also confirmed in primary cell culture, in which both RGC survival and neurite outgrowth were compromised. Importantly, RGC loss was clearly associated with a decline in visual performance. A subsequent electroporation with wildtype ND4 prevented both RGC loss and the impairment of visual function. Ellouze et al. (2008) concluded that their data provided the proof of principle that optimized allotopic expression can be an effective treatment for LHON, and that they opened the way to clinical studies of other devastating mitochondrial disorders. </p><p>By studying the penetrance of LHON in 1,859 individuals from 182 Chinese families (including 1 from Cambodia) with the MTND4 11778G-A mutation, Ji et al. (2008) found that mitochondrial haplogroup M7b1-prime-2 was associated with increased risk of visual loss, whereas the M8a haplogroup was associated with decreased risk of visual loss. Further sequence analysis suggested that the M7b1-prime-2 effect was due to variation in the MTND5 (516005) gene, and that the M8a effect was due to variation in the MTATP6 gene (516060). </p><p>See LOAM (308905) for discussion of a form of LHON with increased penetrance and earlier age of onset resulting from additional mutation in the PRICKLE3 gene (300111.0001) acting as a modifier of disease expression.</p>
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<h4>
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<span class="mim-font">
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<strong>.0002 MELAS SYNDROME</strong>
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MTND4, MELAS11084G
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SNP: rs199476113,
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ClinVar: RCV000010355, RCV000854703
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<span class="mim-text-font">
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<p>This allele changes the moderately conserved threonine at amino acid 109 to an alanine (T109A). It was found in a 19-year-old female with a history of intermittent migraines, sensorineural hearing loss, bilateral cataracts, grand mal seizures, stroke-like episodes, lactic acidosis, and ragged-red muscle fibers (MELAS syndrome; 540000). An older brother and the mother had milder symptoms (Danks et al., 1988; Lertrit et al., 1992). Later this mutation was found in 14% of Asians, which suggests that it may be a polymorphism (Sakuta et al., 1993) and not related to the MELAS (540000)-like symptoms of this family. </p>
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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 class="mim-text-font">
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MTND4, VAL312ILE
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<br />
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SNP: rs200873900,
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ClinVar: RCV000010356, RCV000055697, RCV000854742
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<span class="mim-text-font">
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<p>Hereditary spastic dystonia and LHON (see 535000 and 500001), manifested either separately or in combination, had occurred among 24 individuals over 7 generations of a large Dutch family (Bruyn et al., 1992). Both the dystonia and LHON showed strict maternal inheritance. Of the maternal relatives, 12 had optic atrophy only, 4 exhibited exclusively the neurologic disorder (1 with unilateral involvement), and 8 presented with optic atrophy and the neurologic disorder; 1 of these 8 had a unilateral neurologic deficit. De Vries et al. (1996) found 2 previously unreported mtDNA mutations. One was a heteroplasmic A-to-G transition at nucleotide 11696 in the ND4 gene that resulted in substitution of an isoleucine for valine at amino acid position 312. The second mutation, a homoplasmic T-to-A transition at nucleotide position 14596 in the ND6 gene (516006.0003), resulted in the substitution of a methionine for the isoleucine at amino acid residue 26. Biochemical analysis of a muscle biopsy revealed severe complex I deficiency. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 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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MTND4, 11777C-A
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<br />
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SNP: rs28384199,
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ClinVar: RCV000010357, RCV000144013, RCV000854746, RCV002260594
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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 67-year-old man with cognitive deficits, status epilepticus, hemiparesis, and severe lactic acidosis, Deschauer et al. (2003) identified a heteroplasmic 11777C-A mutation in the MTND4 gene. Respiratory chain analysis of skeletal muscle showed a defect in the activity of complex I (40% of control) (252010). The authors noted that the patient had stroke-like symptoms similar to those observed in the MELAS syndrome (540000) but with later onset. The mutation occurred in the same codon as the 11778G-A mutation (516003.0001) that causes Leber hereditary optic neuropathy. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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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Johns et al. (1992); Mashima et al. (1993); Montoya et al. (1981);
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Nakamura et al. (1992)
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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<strong>Analysis of mitochondrial ND4 gene DNA sequence in Finnish families with Leber hereditary optic neuroretinopathy.</strong>
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Wallace, D. C., Singh, G., Lott, M. T., Hodge, J. A., Schurr, T. G., Lezza, A. M., Elsas, L. J., Nikoskelainen, E. K.
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Yoneda, M., Tsuji, S., Yamauchi, T., Inuzuka, T., Miyatake, T., Horai, S., Ozawa, T.
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<strong>Mitochondrial DNA mutation in family with Leber's hereditary optic neuropathy.</strong>
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