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- *516000 - COMPLEX I, SUBUNIT ND1; MTND1
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- OMIM
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<p>
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<span class="h4">*516000</span>
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<br />
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<strong>Table of Contents</strong>
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<li role="presentation">
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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="#evolution">Evolution</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/516000">Table View</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000198888;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-ND1" 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=4535" 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=516000" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000198888;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=516000" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.proteinatlas.org/search/MT-ND1" 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/128641,337189,251831107" 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/P03886" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=4535" 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=ENSG00000198888;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-ND1" 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-ND1" 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+4535" 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-ND1" 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:4535" 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/4535" 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:7455" 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-nd1" 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=516000[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-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><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=516000[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/MT-ND1/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000198888" 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-ND1" 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-ND1" 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-ND1&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/PA31259" 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-cell;">Animal Models</div>
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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:7455" 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/FBgn0013679.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:101787" 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-ND1#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:101787" 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/4535/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=4535" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:516000" 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:4535" 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-ND1&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> 26929004, 39925003, 49049000, 51178009, 58610003<br />
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<strong>ICD10CM:</strong> E88.41, G20, G20.A1, G30, G30.9, H47.22<br />
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<strong>ICD9CM:</strong> 331.0, 332, 332.0, 798.0<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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516000
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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 ND1; MTND1
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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 ND1<br />
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NADH DEHYDROGENASE, SUBUNIT 1
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</span>
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</h4>
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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="includedTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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MITOCHONDRIAL COMPLEX I DEFICIENCY, MITOCHONDRIAL TYPE 3, INCLUDED; MC1DM3, INCLUDED
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</span>
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</div>
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<div>
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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-ND1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">MT-ND1</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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</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 1 is one of 7 mitochondrial DNA (mtDNA) encoded subunits (MTND1, MTND2, MTND3, MTND4, MTND4L, 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="#56" 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="#4" 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="#61" class="mim-tip-reference" title="Walker, J. E., Arizmendi, J. M., Dupuis, A., Fearnley, I. M., Finel, M., Medd, S. M., Pilkington, S. J., Runswick, M. J., Skehel, J. M. <strong>Sequences of 20 subunits of NADH:ubiquinone oxidoreductase from bovine heart mitochondria. Application of a novel strategy for sequencing proteins using the polymerase chain reaction.</strong> J. Molec. Biol. 226: 1051-1072, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1518044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1518044</a>] [<a href="https://doi.org/10.1016/0022-2836(92)91052-q" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1518044">Walker et al., 1992</a>; <a href="#3" 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="#5" 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="#15" class="mim-tip-reference" title="Chomyn, A., Mariottini, P., Cleeter, M. W. J., Ragan, C. I., Matsuno-Yagi, A., Hatefi, Y., Doolittle, R. G., Attardi, G. <strong>Six unidentified reading frames of human mitochondrial DNA encode components of the respiratory-chain NADH dehydrogenase.</strong> Nature 314: 592-597, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3921850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3921850</a>] [<a href="https://doi.org/10.1038/314592a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3921850">1985</a>, <a href="#14" class="mim-tip-reference" title="Chomyn, A., Cleeter, M. 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, 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="#63" 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: 461-481, 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="#47" 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="#62" 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=1426273+7219534+1518044+3764430+3921850+6955589+3518425+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><p>Complex I is the first step in the electron transport chain of mitochondrial oxidative phosphorylation (OXPHOS) and is located within the mitochondrial inner membrane. It accepts electrons from NADH and transfers them, through a series of electron carriers, to ubiquinone (Coenzyme Q10). The internal electron carriers of complex I include flavin mononucleotide (FMN) and 6 iron-sulfur clusters designated N-1a, N-1b, N-2, N-3, N-4, and N-5 (<a href="#44" class="mim-tip-reference" title="Ohnishi, T. <strong>Mitochondrial iron-sulfur flavohydrogenases.In: Capaldi, R. A. (ed.) : Membrane Proteins in Energy Transduction.</strong> New York: Dekker (pub.) 1979."None>Ohnishi, 1979</a>; <a href="#53" 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>). Complex I can be subdivided into 3 main fractions: the flavoprotein fragment, the iron-protein fragment, and the hydrophobic protein fragment (<a href="#53" 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>). The flavoprotein fragment contains the FMN, 6 of the iron atoms, and 3 polypeptides (51, 24, and 10 kD) (<a href="#18" class="mim-tip-reference" title="Galante, Y. M., Hatefi, Y. <strong>Purification and molecular and enzymic properties of mitochondrial NADH dehydrogenase.</strong> Arch. Biochem. Biophys. 192: 559-568, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35108</a>] [<a href="https://doi.org/10.1016/0003-9861(79)90126-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35108">Galante and Hatefi, 1979</a>; <a href="#51" class="mim-tip-reference" title="Ragan, C. I., Galante, Y. M., Hatefi, Y., Ohnishi, T. <strong>Resolution of mitochondrial NADH dehydrogenase and isolation of two iron-sulfur proteins.</strong> Biochemistry 21: 590-594, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6279147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6279147</a>] [<a href="https://doi.org/10.1021/bi00532a027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6279147">Ragan et al., 1982</a>). The NADH-binding site and FMN have been assigned to the 51-kD polypeptide (<a href="#13" class="mim-tip-reference" title="Chen, S., Guillory, R. J. <strong>Studies on the interaction of arylazido-beta-alanyl NAD+ with the mitochondrial NADH dehydrogenase.</strong> J. Biol. Chem. 256: 8318-8323, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7263655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7263655</a>]" pmid="7263655">Chen and Guillory, 1981</a>). The iron-protein fragment contains 9 or 10 iron atoms (<a href="#51" class="mim-tip-reference" title="Ragan, C. I., Galante, Y. M., Hatefi, Y., Ohnishi, T. <strong>Resolution of mitochondrial NADH dehydrogenase and isolation of two iron-sulfur proteins.</strong> Biochemistry 21: 590-594, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6279147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6279147</a>] [<a href="https://doi.org/10.1021/bi00532a027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6279147">Ragan et al., 1982</a>), and a 15-kD protein from this fragment appears to be the ubiquinone-binding protein involved in electron transfer to ubiquinone (<a href="#59" class="mim-tip-reference" title="Suzuki, H., Ozawa, T. <strong>An ubiquinone-binding protein in mitochondrial NADH-ubiquinone reductase (Complex I).</strong> Biochem. Biophys. Res. Commun. 138: 1237-12422, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3092820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3092820</a>] [<a href="https://doi.org/10.1016/s0006-291x(86)80415-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3092820">Suzuki and Ozawa, 1986</a>). The MTND6 protein may also be located in the iron-protein fragment (<a href="#14" class="mim-tip-reference" title="Chomyn, A., Cleeter, M. 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, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3764430/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3764430</a>] [<a href="https://doi.org/10.1126/science.3764430" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3764430">Chomyn et al., 1986</a>). The hydrophobic protein fragment contains the iron-sulfur centers that are the likely electron donors to ubiquinone (<a href="#43" class="mim-tip-reference" title="Ohnishi, T., Ragan, C. I., Hatefi, Y. <strong>EPR studies of iron-sulfur clusters in isolated subunits and subfractions of NADH-ubiquinone oxidoreductase.</strong> J. Biol. Chem. 260: 2782-2788, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2982836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2982836</a>]" pmid="2982836">Ohnishi et al., 1985</a>; <a href="#42" class="mim-tip-reference" title="Ohnishi, T., Leigh, J. S., Ragan, C. I., Racker, E. <strong>Low temperature electron paramagnetic resonance studies on iron centers in cardiac NADH dehydrogenase.</strong> Biochem. Biophys. Res. Commun. 56: 775-782, 1974."None>Ohnishi et al., 1974</a>). Of the 7 mitochondrial DNA Complex I genes, the gene products for MTND1, MTND3, and MTND4L have been localized to the hydrophobic protein fragment (<a href="#53" 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>), and the MTND2, MTND4, and MTND5 gene products probably reside there also. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7263655+2982836+3764430+3092820+35108+6279147" 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 MTND1 polypeptide binds rotenone and rotenone analogs, and rotenone is thought to interact with the ubiquinone binding site. Hence, MTND1 might be involved in electron transfer to ubiquinone (<a href="#53" 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="#17" class="mim-tip-reference" title="Earley, F. G., Ragan, C. I. <strong>Photoaffinity labelling of mitochondrial NADH dehydrogenase with arylazidoamorphigenin, an analogue of rotenone.</strong> Biochem. J. 224: 525-534, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6517863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6517863</a>] [<a href="https://doi.org/10.1042/bj2240525" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6517863">Earley and Ragan, 1984</a>). However, studies on erythrosine-5-prime-iodoacetamide binding suggest that the rotenone and ubiquinone binding sites may not be identical (<a href="#2" class="mim-tip-reference" title="Ahmed, I., Krishnamoorthy, G. <strong>The non-equivalence of binding sites of coenzyme quinone and rotenone in mitochondrial NADH-CoQ reductase.</strong> FEBS Lett. 300: 275-278, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1313376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1313376</a>] [<a href="https://doi.org/10.1016/0014-5793(92)80862-b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1313376">Ahmed and Krishnamoorthy, 1992</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1313376+6517863" 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>MTND1 is encoded by the guanine-rich heavy (H) strand of the mtDNA between nucleotide pairs (nps) 3307 and 4262 (<a href="#3" 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="#62" class="mim-tip-reference" title="Wallace, D. C., Lott, M. T., Torroni, A., Brown, M. D., Shoffner, J. M. <strong>Report of the committee on human mitochondrial DNA.In: Cuticchia, A. J.; Pearson, P. L. (eds.) : Human Gene Mapping, 1993: A Compendium.</strong> Baltimore: Johns Hopkins Univ. Press (pub.) 1994. Pp. 813-845."None>Wallace et al., 1994</a>). It is maternally inherited along with the mtDNA (<a href="#19" class="mim-tip-reference" title="Giles, R. E., Blanc, H., Cann, H. M., Wallace, D. C. <strong>Maternal inheritance of human mitochondrial DNA.</strong> Proc. Nat. Acad. Sci. 77: 6715-6719, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6256757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6256757</a>] [<a href="https://doi.org/10.1073/pnas.77.11.6715" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6256757">Giles et al., 1980</a>; <a href="#12" 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=6261411+7219534+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 MTND1 gene encompasses 955 nps of continuous coding sequence. It contains no introns, has a two-base (AC) 5-prime noncoding sequence, an ATA methionine start codon, and ends with the UA of the UAA termination codon (<a href="#3" 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="#38" class="mim-tip-reference" title="Montoya, J., Ojala, D., Attardi, G. <strong>Distinctive features of the 5'-terminal sequences of the human mitochondrial mRNAs.</strong> Nature 290: 465-470, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7219535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7219535</a>] [<a href="https://doi.org/10.1038/290465a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7219535">Montoya et al., 1981</a>; <a href="#45" class="mim-tip-reference" title="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>). It is transcribed as part of the polycistronic H-strand transcript, flanked by tRNALeuUUR and tRNAIle. The tRNAs fold within the transcript and are processed out freeing transcript 13, the MTND1 mRNA. This mRNA is then polyadenylated completing the termination codon (<a href="#3" class="mim-tip-reference" title="Anderson, S., Bankier, A. T., Barrell, B. G., de Bruijn, M. H. L., Coulson, A. R., Drouin, J., Eperon, I. C., Nierlich, D. P., Roe, B. A., Sanger, F., Schreier, P. H., Smith, A. J. H., Staden, R., Young, I. G. <strong>Sequence and organization of the human mitochondrial genome.</strong> Nature 290: 457-465, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7219534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7219534</a>] [<a href="https://doi.org/10.1038/290457a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7219534">Anderson et al., 1981</a>; <a href="#45" class="mim-tip-reference" title="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="#6" 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="https://pubmed.ncbi.nlm.nih.gov/?term=7219535+7219534+7140372+7219536" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The predicted polypeptide has a molecular weight of 35.6 kD (<a href="#3" 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="#62" 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>), but its apparent MW is 29.5 kD on SDS-polyacrylamide gels (PAGE) using Tris-glycine buffer (<a href="#46" class="mim-tip-reference" title="Oliver, N. A., McCarthy, J., Wallace, D. C. <strong>Comparison of mitochondrially synthesized polypeptides of human, mouse, and monkey cell lines by a two-dimensional protease gel system.</strong> Somat. Cell Molec. Genet. 10: 639-643, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6438810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6438810</a>] [<a href="https://doi.org/10.1007/BF01535230" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6438810">Oliver et al., 1984</a>; <a href="#47" 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="#63" 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: 461-481, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3518425/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3518425</a>]" pmid="3518425">Wallace et al., 1986</a>) and 24 kD on SDS-PAGE using urea-phosphate buffer (<a href="#16" class="mim-tip-reference" title="Chomyn, A., Mariottini, P., Gonzalez-Cadavid, N., Attardi, G., Strong, D. D., Trovato, D., Riley, M., Doolittle, R. F. <strong>Identification of the polypeptides encoded in the ATPase 6 gene and in the unassigned reading frames 1 and 3 of human mtDNA.</strong> Proc. Nat. Acad. Sci. 80: 5535-5539, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6225122/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6225122</a>] [<a href="https://doi.org/10.1073/pnas.80.18.5535" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6225122">Chomyn et al., 1983</a>; <a href="#62" 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>). The amino terminal 17 amino acids have been shown in mouse to code for a polymorphic cell surface antigen (<a href="#36" class="mim-tip-reference" title="Loveland, B., Wang, C. R., Yonekawa, H., Hermel, E., Fischer-Lindahl, D. <strong>Maternally transmitted histocompatibility antigen of mice: A hydrophobic peptide of a mitochondrially encoded protein..</strong> Cell 60: 971-980, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2317868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2317868</a>] [<a href="https://doi.org/10.1016/0092-8674(90)90345-f" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2317868">Loveland et al., 1990</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6225122+7219534+6438810+6955589+3518425+2317868" 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="#3" 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 +3391, -3537, +3981; Dde I: +3388, -3534, +3846, +3930; Hae III: -3315, +3391, -3412, +3624, +3624/3833/9253, +3714/3744, +3744, +3842, -3849, +4092; Hha I: -3698; HincII: +3659, +3759; HinfI: +3359, +4092; Hpa I: +3592; Mbo I: -3569, +4026; Rsa I: -3337, +3371, +3397, +3987, +4051; Taq I: +3868, +3899, -3944 (<a href="#62" 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>Allelic variants of MTND1 have been reported in several disorders, including Leber hereditary optic neuropathy (LHON; <a href="/entry/535000">535000</a>), Alzheimer disease (see <a href="/entry/104300">104300</a> and <a href="/entry/502500">502500</a>), and Parkinson disease (PD; see <a href="/entry/168600">168600</a>).</p><p><a href="#48" class="mim-tip-reference" title="Opdal, S. H., Rognum, T. O., Torgersen, H., Vege, A. <strong>Mitochondrial DNA point mutations detected in four cases of sudden infant death syndrome.</strong> Acta Paediat. 88: 957-960, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10519336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10519336</a>] [<a href="https://doi.org/10.1080/08035259950168441" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10519336">Opdal et al. (1999)</a> reported point mutations in the MTND1 gene as a cause of sudden infant death syndrome (SIDS; <a href="/entry/272120">272120</a>); see <a href="#0008">516000.0008</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10519336" 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="#39" class="mim-tip-reference" title="Munakata, K., Tanaka, M., Mori, K., Washizuka, S., Yoneda, M., Tajima, O., Akiyama, T., Nanko, S., Kunugi, H., Tadokoro, K., Ozaki, N., Inada, T., Sakamoto, K., Fukunaga, T., Iijima, Y., Iwata, N., Tatsumi, M., Yamada, K., Yoshikawa, T., Kato, T. <strong>Mitochondrial DNA 3644T-C mutation associated with bipolar disorder.</strong> Genomics 84: 1041-1050, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15533721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15533721</a>] [<a href="https://doi.org/10.1016/j.ygeno.2004.08.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15533721">Munakata et al. (2004)</a> examined the entire sequence of mtDNA in 6 subjects with bipolar disorder and comorbid somatic symptoms suggestive of mitochondrial disorders and identified several uncharacterized homoplastic nonsynonymous nucleotide substitutions. Of these, a 3644T-C mutation in the MTND1 gene was found in 5 of 199 patients with bipolar disorder (see <a href="/entry/125480">125480</a>) but in none of 258 controls (p = 0.015). The 3644T-C mutation converts amino acid 113, valine, to alanine. <a href="#39" class="mim-tip-reference" title="Munakata, K., Tanaka, M., Mori, K., Washizuka, S., Yoneda, M., Tajima, O., Akiyama, T., Nanko, S., Kunugi, H., Tadokoro, K., Ozaki, N., Inada, T., Sakamoto, K., Fukunaga, T., Iijima, Y., Iwata, N., Tatsumi, M., Yamada, K., Yoshikawa, T., Kato, T. <strong>Mitochondrial DNA 3644T-C mutation associated with bipolar disorder.</strong> Genomics 84: 1041-1050, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15533721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15533721</a>] [<a href="https://doi.org/10.1016/j.ygeno.2004.08.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15533721">Munakata et al. (2004)</a> noted that val113 is well conserved from Drosophila to mammalian species. Using transmitochondrial cybrids, they found that the mutation decreased mitochondrial membrane potential and complex I activity compared to haplogroup-matched controls. <a href="#39" class="mim-tip-reference" title="Munakata, K., Tanaka, M., Mori, K., Washizuka, S., Yoneda, M., Tajima, O., Akiyama, T., Nanko, S., Kunugi, H., Tadokoro, K., Ozaki, N., Inada, T., Sakamoto, K., Fukunaga, T., Iijima, Y., Iwata, N., Tatsumi, M., Yamada, K., Yoshikawa, T., Kato, T. <strong>Mitochondrial DNA 3644T-C mutation associated with bipolar disorder.</strong> Genomics 84: 1041-1050, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15533721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15533721</a>] [<a href="https://doi.org/10.1016/j.ygeno.2004.08.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15533721">Munakata et al. (2004)</a> suggested that the mutation might increase the risk for bipolar disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15533721" 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>Mitochondrial genomes exhibit a 20-fold range in protein gene content, from only 3 in the virtually extinct mtDNA of Plasmodium to 61 in Reclinomonas (<a href="#34" class="mim-tip-reference" title="Lang, B. F., Gray, M. W., Burger, G. <strong>Mitochondrial genome evolution and the origin of eukaryotes.</strong> Annu. Rev. Genet. 33: 351-397, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10690412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10690412</a>] [<a href="https://doi.org/10.1146/annurev.genet.33.1.351" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10690412">Lang et al., 1999</a>). However, even Reclinomonas mtDNA encodes only a small fraction of the proteins encoded by the bacterial progenitor of the mitochondrion. <a href="#1" class="mim-tip-reference" title="Adams, K. L., Qiu, Y.-L., Stoutemyer, M., Palmer, J. D. <strong>Punctuated evolution of mitochondrial gene content: high and variable rates of mitochondrial gene loss and transfer to the nucleus during angiosperm evolution.</strong> Proc. Nat. Acad. Sci. 99: 9905-9912, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12119382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12119382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12119382[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.042694899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12119382">Adams et al. (2002)</a> therefore suggested that the great majority of the original set of mitochondrial genes was either transferred to the nucleus or lost entirely from the cell early in eukaryotic evolution, before the emergence of essentially all extant lineages of eukaryotes. Mitochondrial gene loss and functional gene transfer to the nucleus essentially ceased in the common ancestor of animals, more than 600 million years ago, as the many sequenced animal mtDNAs all contain the same 13 protein-encoding genes. Although functional gene transfer has ceased in animals, pseudogenes of mitochondrial origin are common in animal nuclear genomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10690412+12119382" 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">rs199476118 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476118;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=rs199476118" 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=rs199476118" 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=RCV000010370 OR RCV000143998 OR RCV000735416 OR RCV000757484 OR RCV003319165 OR RCV004814877" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010370, RCV000143998, RCV000735416, RCV000757484, RCV003319165, RCV004814877" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010370...</a>
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<p><strong><em>Leber Optic Atrophy</em></strong></p><p>
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The 3460G-A transition in the MTND1 gene converts the modestly conserved alanine 52 to a threonine (A52T). It is sufficient by itself to cause LHON (<a href="/entry/535000">535000</a>), is found in about 15% of Caucasian patients but not controls, has arisen on a variety of genetic backgrounds, can be heteroplasmic, results in vision loss in 14 to 40% of maternal relatives and 33 to 67% of males, and has a 22% visual recovery rate (<a href="#11" class="mim-tip-reference" title="Brown, M. D., Voljavec, A. S., Lott, M. T., Torroni, A., Yang, C.-C., Wallace, D. C. <strong>Mitochondrial DNA complex I and III mutations associated with Leber's hereditary optic neuropathy.</strong> Genetics 130: 163-173, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1732158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1732158</a>] [<a href="https://doi.org/10.1093/genetics/130.1.163" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1732158">Brown et al., 1992</a>; <a href="#23" class="mim-tip-reference" title="Howell, N., Bindoff, L. A., McCullough, D. A., Kubacka, I., Poulton, J., Mackey, D., Taylor, L., Turnbull, D. M. <strong>Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees.</strong> Am. J. Hum. Genet. 49: 939-950, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1928099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1928099</a>]" pmid="1928099">Howell et al., 1991</a>; <a href="#25" 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)</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="#26" class="mim-tip-reference" title="Huoponen, K., Vilkki, J., Aula, P., Nikoskelainen, E. K., Savontaus, M. L. <strong>A new mtDNA mutation associated with Leber hereditary optic neuroretinopathy.</strong> Am. J. Hum. Genet. 48: 1147-1153, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1674640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1674640</a>]" pmid="1674640">Huoponen et al., 1991</a>; <a href="#31" class="mim-tip-reference" title="Johns, D. R. <strong>Mitochondrial ND-1 mutation in Leber hereditary optic neuropathy.</strong> Am. J. Hum. Genet. 50: 872-874, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1550131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1550131</a>]" pmid="1550131">Johns, 1992</a>; <a href="#30" 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.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1444915/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1444915</a>] [<a href="https://doi.org/10.1001/archopht.1992.01080230077025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1444915">Johns et al., 1992</a>; <a href="#37" 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>; <a href="#49" class="mim-tip-reference" title="Paulus, W., Straube, A., Bauer, W., Harding, A. E. <strong>Central nervous system involvement in Leber's optic neuropathy.</strong> J. Neurol. 240: 251-253, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8496715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8496715</a>] [<a href="https://doi.org/10.1007/BF00818714" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8496715">Paulus et al., 1993</a>) <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1928099+1732158+1674640+8496715+1734726+1444915+1550131+1959619" 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="#65" 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 (<a href="/entry/516003#0001">516003.0001</a>), and the most severe LHON mutation, 3460. 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="#65" 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="#27" class="mim-tip-reference" title="Jaros, E., Mahad, D. J., Hudson, G., Birchall, D., Sawcer, S. J., Griffiths, P. G., Sunter, J., Compston, D. A. S., Perry, R. H., Chinnery, P. F. <strong>Primary spinal cord neurodegeneration in Leber hereditary optic neuropathy.</strong> Neurology 69: 214-216, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17620555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17620555</a>] [<a href="https://doi.org/10.1212/01.wnl.0000265598.76172.59" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17620555">Jaros et al. (2007)</a> reported a 39-year-old woman with severe complicated LHON who developed progressive gait and sensory disturbances 5 years after onset of subacute bilateral visual failure. Visual symptoms included loss of acuity, central scotomata, optic atrophy, and nystagmus. She also had symmetric pyramidal-pattern lower limb weakness, hyperreflexia, and distal loss of vibratory sensation. Brain MRI showed symmetric high T2 signals in the substantia nigra, pons, and dorsal columns of the spinal cord. After an unexpected death, postmortem examination showed myelin loss and macrophage activation in the posterior columns of the upper spinal cord and neurodegeneration at multiple levels. Molecular analysis detected a homoplasmic 3460G-A mutation in blood and spinal cord. Her mtDNA haplotype H and HLA-DR8 status did not explain the severe phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17620555" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Mitochondrial Complex I Deficiency, Mitochondrial Type 3</em></strong></p><p>
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<a href="#22" class="mim-tip-reference" title="Hinttala, R., Smeets, R., Moilanen, J. S., Ugalde, C., Uusimaa, J., Smeitink, J. A. M., Majamaa, K. <strong>Analysis of mitochondrial DNA sequences in patients with isolated or combined oxidative phosphorylation system deficiency. (Letter)</strong> J. Med. Genet. 43: 881-886, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16738010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16738010</a>] [<a href="https://doi.org/10.1136/jmg.2006.042168" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16738010">Hinttala et al. (2006)</a> identified a homoplasmic 3460G-A mutation in skeletal muscle from an 18-year-old woman with severe mitochondrial complex I deficiency (MC1DM3) manifest as a progressive myopathy starting at age 10 years. She was wheelchair-bound with normal mental functioning. Her younger brother developed classic LHON. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16738010" 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">rs199476119 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476119;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=rs199476119" 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=rs199476119" 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=RCV000010372 OR RCV004595480" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010372, RCV004595480" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010372...</a>
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<p>This allele converts the highly conserved leucine 285 to a proline (L285P). This mutation has been found in 1 large Australian pedigree manifesting LHON (<a href="/entry/535000">535000</a>) and additional neurological symptoms, together with the primary MTND6*LHON14484C. The mutation was homoplasmic in that pedigree in which 76% of the maternal relatives were affected, 54% of which were males (<a href="#23" class="mim-tip-reference" title="Howell, N., Bindoff, L. A., McCullough, D. A., Kubacka, I., Poulton, J., Mackey, D., Taylor, L., Turnbull, D. M. <strong>Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees.</strong> Am. J. Hum. Genet. 49: 939-950, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1928099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1928099</a>]" pmid="1928099">Howell et al., 1991</a>). See also variant <a href="#0006">516000.0006</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1928099" 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">rs1599988 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1599988;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=rs1599988" 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=rs1599988" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>This allele changes the weakly conserved tyrosine at amino acid 304 to a histidine (Y304H) and is found in about 40% of the mtDNAs of European LHON (<a href="/entry/535000">535000</a>) patients. It has been found in association with 1 of 4 primary LHON mutations (MTND4*LHON11778A, MTND1*LHON3460A; MTND6*LHON14484A, and MTCYB*LHON15257A) as well as with the MTND5*LHON13708A and MTND2*LHON4917G secondary mutations. It is also found in 13% of the general population and hence is most likely a linked polymorphism (<a href="#11" class="mim-tip-reference" title="Brown, M. D., Voljavec, A. S., Lott, M. T., Torroni, A., Yang, C.-C., Wallace, D. C. <strong>Mitochondrial DNA complex I and III mutations associated with Leber's hereditary optic neuropathy.</strong> Genetics 130: 163-173, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1732158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1732158</a>] [<a href="https://doi.org/10.1093/genetics/130.1.163" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1732158">Brown et al., 1992</a>; <a href="#28" 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>) <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1900003+1732158" 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">rs41460449 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs41460449;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=rs41460449" 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=rs41460449" 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=RCV000010375 OR RCV000507319 OR RCV000853650 OR RCV004814878" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010375, RCV000507319, RCV000853650, RCV004814878" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010375...</a>
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<p>This mutation converts the highly conserved tyrosine at amino acid 30 to a histidine (Y30H). The mutation is rare among European LHON (<a href="/entry/535000">535000</a>) patients and found in about 0.9% of controls. It has only been observed on 1 haplotype and when combined with MTND6*LHON14484A is associated with blindness in 37% of maternal relatives, 100% of which are males. Patients with this genotype have an approximately 30% recovery rate (<a href="#11" class="mim-tip-reference" title="Brown, M. D., Voljavec, A. S., Lott, M. T., Torroni, A., Yang, C.-C., Wallace, D. C. <strong>Mitochondrial DNA complex I and III mutations associated with Leber's hereditary optic neuropathy.</strong> Genetics 130: 163-173, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1732158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1732158</a>] [<a href="https://doi.org/10.1093/genetics/130.1.163" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1732158">Brown et al., 1992</a>; <a href="#30" 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.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1444915/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1444915</a>] [<a href="https://doi.org/10.1001/archopht.1992.01080230077025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1444915">Johns et al., 1992</a>; <a href="#41" class="mim-tip-reference" title="Obayashi, T., Hattori, K., Sugiyama, S., Tanaka, M., Tanaka, T., Itoyama, S., Deguchi, H., Kawamura, K., Koga, Y., Toshima, H., Takeda, N., Nagano, M., Ito, T., Ozawa, T. <strong>Point mutations in mitochondrial DNA in patients with hypertrophic cardiomyopathy.</strong> Am. Heart J. 124: 1263-1269, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1442494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1442494</a>] [<a href="https://doi.org/10.1016/0002-8703(92)90410-w" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1442494">Obayashi et al., 1992</a>) <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1442494+1444915+1732158" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 ALZHEIMER DISEASE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199476120 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476120;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=rs199476120" 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=rs199476120" 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=RCV000010376 OR RCV000010377 OR RCV000853653" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010376, RCV000010377, RCV000853653" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010376...</a>
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<p>This allele converts the highly conserved methionine at amino acid 31 to a valine (M31V). It has been identified in 2 Caucasian pedigrees showing matrilineal transmission of Alzheimer disease (<a href="/entry/502500">502500</a>). One of these pedigrees also harbored the MTTQ*ADPD4336G mutation found in 5.2% of AD+PD (<a href="/entry/168600">168600</a>) patients but only in 0.4% of controls. The MTND1*ADPD3397G mutation was not found in 248 Caucasian controls, but was found in 1 Asian and in several members of the Ticuna Indian tribe of the Amazon (<a href="#55" class="mim-tip-reference" title="Shoffner, J. M., Brown, M. D., Torroni, A., Lott, M. T., Cabell, M. F., Mirra, S. S., Beal, M. F., Yang, C., Gearing, M., Salvo, R., Watts, R. L., Juncos, J. L., Hansen, L. A., Crain, B. J., Fayad, M., Reckord, C. L., Wallace, D. C. <strong>Mitochondrial DNA variants observed in Alzheimer disease and Parkinson disease patients.</strong> Genomics 17: 171-184, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8104867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8104867</a>] [<a href="https://doi.org/10.1006/geno.1993.1299" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8104867">Shoffner et al., 1993</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8104867" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 LEBER OPTIC ATROPHY</strong>
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MTND1, LHON4136G
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199476121 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476121;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=rs199476121" 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=rs199476121" 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=RCV000010378 OR RCV000853739 OR RCV004713168" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010378, RCV000853739, RCV004713168" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010378...</a>
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<p>This allele converts the moderately conserved tyrosine at amino acid 277 to a cysteine (T277C). It was found in a sub-branch of the Australian LHON (<a href="/entry/535000">535000</a>) pedigree in association with mutations MTDN1*LHON4160C (<a href="#0002">516000.0002</a>) and MTND6*14484C (<a href="/entry/516006#0001">516006.0001</a>). This mutation has been proposed to ameliorate partially the symptoms of the latter (<a href="#23" class="mim-tip-reference" title="Howell, N., Bindoff, L. A., McCullough, D. A., Kubacka, I., Poulton, J., Mackey, D., Taylor, L., Turnbull, D. M. <strong>Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees.</strong> Am. J. Hum. Genet. 49: 939-950, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1928099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1928099</a>]" pmid="1928099">Howell et al., 1991</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1928099" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 COLORECTAL CANCER</strong>
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SUDDEN INFANT DEATH SYNDROME, INCLUDED
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MTND1, 3308T-C, MET1THR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28358582 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28358582;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=rs28358582" 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=rs28358582" 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=RCV000010379 OR RCV000010380 OR RCV000239184 OR RCV000853627" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010379, RCV000010380, RCV000239184, RCV000853627" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010379...</a>
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<p>Early on, <a href="#64" class="mim-tip-reference" title="Warburg, O. <strong>On the origin of cancer cells.</strong> Science 123: 309-314, 1956.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13298683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13298683</a>] [<a href="https://doi.org/10.1126/science.123.3191.309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13298683">Warburg (1956)</a> suggested that alterations of oxidative phosphorylation in tumor cells played a causative role in cancerous growth. Interest in the mitochondria with regard to neoplasia has revived, largely because of their role in apoptosis and other aspects of tumor biology. The mitochondrial genome is particularly susceptible to mutations because of the high level of reactive oxygen species (ROS) generated in this organelle, coupled with a low level of DNA repair. <a href="#50" class="mim-tip-reference" title="Polyak, K., Li, Y., Zhu, H., Lengauer, C., Willson, J. K. V., Markowitz, S. D., Trush, M. A., Kinzler, K. W., Vogelstein, B. <strong>Somatic mutations of the mitochondrial genome in human colorectal tumours.</strong> Nature Genet. 20: 291-293, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9806551/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9806551</a>] [<a href="https://doi.org/10.1038/3108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9806551">Polyak et al. (1998)</a> analyzed the complete mtDNA genome of 10 human colorectal cancer (<a href="/entry/114500">114500</a>) cell lines by sequencing and found mutations in 7 (70%). The majority of mutations were transitions at purines, consistent with a ROS-related derivation. These mutations were somatic, and those evaluated occurred in the primary tumor from which the cell line was derived. Most of the mutations were homoplasmic, indicating that the mutant genome was dominant at the intracellular and intercellular levels. One of the mutations occurred in the MTND1 gene, a 3308T-C nucleotide substitution resulting in a met1-to-thr change in the MTND1 protein product. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=13298683+9806551" 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="#54" class="mim-tip-reference" title="Rocha, H., Flores, C., Campos, Y., Arenas, J., Vilarinho, L., Santorelli, F. M., Torroni, A. <strong>About the 'pathological' role of mtDNA T3308C mutation. (Letter)</strong> Am. J. Hum. Genet. 65: 1457-1459, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10521313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10521313</a>] [<a href="https://doi.org/10.1086/302641" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10521313">Rocha et al. (1999)</a> concluded that the 3308T-C mutation is an ancient marker of a common West African haplogroup. They found that all Iberian subjects with this mutation who were affected by mitochondrial encephalomyopathies harbored a particular mtDNA haplogroup. They pointed out that elimination of the methionine codon AUA at position 1 of the ND1 subunit is common in some human populations, suggesting that the maintenance of that codon is not critical in our species. Possibly this is because the third codon (AUG) of the human ND1 subunit also encodes for a methionine, and the ND1 subunit of the particular haplogroup observed in Iberian patients, although shortened by 2 amino acids, may still retain its functionality. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10521313" 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 <a href="#0008">516000.0008</a> and <a href="#48" class="mim-tip-reference" title="Opdal, S. H., Rognum, T. O., Torgersen, H., Vege, A. <strong>Mitochondrial DNA point mutations detected in four cases of sudden infant death syndrome.</strong> Acta Paediat. 88: 957-960, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10519336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10519336</a>] [<a href="https://doi.org/10.1080/08035259950168441" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10519336">Opdal et al. (1999)</a> for evidence that the 3308T-C mutation can result in sudden infant death syndrome (SIDS; <a href="/entry/272120">272120</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10519336" 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">rs28358582 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28358582;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=rs28358582" 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=rs28358582" 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=RCV000010381 OR RCV000853629" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010381, RCV000853629" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010381...</a>
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<p><a href="#48" class="mim-tip-reference" title="Opdal, S. H., Rognum, T. O., Torgersen, H., Vege, A. <strong>Mitochondrial DNA point mutations detected in four cases of sudden infant death syndrome.</strong> Acta Paediat. 88: 957-960, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10519336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10519336</a>] [<a href="https://doi.org/10.1080/08035259950168441" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10519336">Opdal et al. (1999)</a> investigated the MTTL1 gene (<a href="/entry/590050">590050</a>) and the first part of the MTND1 gene in 158 cases of sudden infant death syndrome (SIDS; <a href="/entry/272120">272120</a>) and 97 controls. The basepairs in the range of 3230 to 3330 were investigated using PCR and temporal temperature gradient electrophoresis (TTGE). If a band shift was detected by TTGE, the area was investigated and the D-loop was sequenced. Three different point mutations (3290T-C in the MTTL1 gene (<a href="/entry/590050#0009">590050.0009</a>), and 3308T-C (<a href="#0007">516000.0007</a>) and 3308T-G in the MTND1 gene) were detected in 4 of the SIDS cases, while none of the controls was mutated. They also found a high D-loop substitution rate in these 4 cases. <a href="#48" class="mim-tip-reference" title="Opdal, S. H., Rognum, T. O., Torgersen, H., Vege, A. <strong>Mitochondrial DNA point mutations detected in four cases of sudden infant death syndrome.</strong> Acta Paediat. 88: 957-960, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10519336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10519336</a>] [<a href="https://doi.org/10.1080/08035259950168441" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10519336">Opdal et al. (1999)</a> suggested that the findings indicated that mtDNA mutations may play a role in some cases of SIDS. They pointed out that a 3250T-C mutation in the MTTL1 gene (<a href="/entry/590050#0008">590050.0008</a>) had been detected in a family in which a sister of the proband and a maternal uncle died of SIDS, and that a 3303C-T mutation in the MTTL1 gene (<a href="/entry/590050#0004">590050.0004</a>) had been detected in a family in which an older brother of the proband died of SIDS. The 3308T-G mutation of the MTND1 gene resulted in a met1-to-ter substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10519336" 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>.0009 MITOCHONDRIAL COMPLEX I DEFICIENCY, MITOCHONDRIAL TYPE 3</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000010383 OR RCV002260595" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010383, RCV002260595" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010383...</a>
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<p><a href="#40" class="mim-tip-reference" title="Musumeci, O., Andreu, A. L., Shanske, S., Bresolin, N., Comi, G. P., Rothstein, R., Schon, E. A., DiMauro, S. <strong>Intragenic inversion of mtDNA: a new type of pathogenic mutation in a patient with mitochondrial myopathy.</strong> Am. J. Hum. Genet. 66: 1900-1904, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10775530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10775530</a>] [<a href="https://doi.org/10.1086/302927" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10775530">Musumeci et al. (2000)</a> studied a 43-year-old man, originally reported by <a href="#8" class="mim-tip-reference" title="Bet, L., Bresolin, N., Moggio, M., Meola, G., Prelle, A., Schapira, A. H., Binzoni, T., Chomyn, A., Fortunato, F., Cerretelli, P., Scarlato, G. <strong>A case of mitochondrial myopathy, lactic acidosis and complex I deficiency.</strong> J. Neurol. 237: 399-404, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2125637/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2125637</a>] [<a href="https://doi.org/10.1007/BF00314729" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2125637">Bet et al. (1990)</a>, who had complained, since childhood, of severe exercise intolerance and myalgia. Morphologic and biochemical studies of muscles showed 40% ragged-red fibers and an approximately 40% reduction of complex I activity consistent with complex I deficiency (MC1DM3). At age 43 years, he still complained of exercise intolerance; neurologic examination showed mild proximal limb weakness but was otherwise normal. His family history was noncontributory. The mother was alive and had always been a very active person. Neither of his 2 sibs complained of exercise intolerance. <a href="#40" class="mim-tip-reference" title="Musumeci, O., Andreu, A. L., Shanske, S., Bresolin, N., Comi, G. P., Rothstein, R., Schon, E. A., DiMauro, S. <strong>Intragenic inversion of mtDNA: a new type of pathogenic mutation in a patient with mitochondrial myopathy.</strong> Am. J. Hum. Genet. 66: 1900-1904, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10775530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10775530</a>] [<a href="https://doi.org/10.1086/302927" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10775530">Musumeci et al. (2000)</a> found an inversion of 7 nucleotides within the ND1 gene, which maintained the reading frame. The inversion, which altered 3 highly conserved amino acids in the polypeptide, was heteroplasmic in the patient's muscle but was not detectable in blood. This was said to be the first report of a pathogenic inversion mutation in human mtDNA. The inversion changed the normal amino acids 199-201 from asp-leu-ala to gly-lys-val. The 7-bp inverted segment was flanked by 8-bp inverted repeats. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10775530+2125637" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Blakely, E. L., Rennie, K. J., Jones, L., Elstner, M., Chrzanowska-Lightowlers, Z. M. A., White, C. B., Shield, J. P. H., Pilz, D. T., Turnbull, D. M., Poulton, J., Taylor, R. W. <strong>Sporadic intragenic inversion of the mitochondrial DNA MTND1 gene causing fatal infantile lactic acidosis.</strong> Pediat. Res. 59: 440-444, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16492986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16492986</a>] [<a href="https://doi.org/10.1203/01.pdr.0000198771.78290.c4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16492986">Blakely et al. (2006)</a> reported a female infant with the same 7-bp inversion in the MTND1 gene described by <a href="#40" class="mim-tip-reference" title="Musumeci, O., Andreu, A. L., Shanske, S., Bresolin, N., Comi, G. P., Rothstein, R., Schon, E. A., DiMauro, S. <strong>Intragenic inversion of mtDNA: a new type of pathogenic mutation in a patient with mitochondrial myopathy.</strong> Am. J. Hum. Genet. 66: 1900-1904, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10775530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10775530</a>] [<a href="https://doi.org/10.1086/302927" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10775530">Musumeci et al. (2000)</a>. However, the infant had a much more severe phenotype and died at age 1 month with marked biventricular hypertrophy, aortic coarctation, and severe lactic acidosis. The mutation was present at high levels in several tissues including the heart (85%), muscle (84%), liver (87%), and cultured skin fibroblasts (70%). Complex I activity was estimated to be 24% of control values. There was no evidence of the mutation or respiratory complex I defect in a muscle biopsy from the patient's mother. <a href="#9" class="mim-tip-reference" title="Blakely, E. L., Rennie, K. J., Jones, L., Elstner, M., Chrzanowska-Lightowlers, Z. M. A., White, C. B., Shield, J. P. H., Pilz, D. T., Turnbull, D. M., Poulton, J., Taylor, R. W. <strong>Sporadic intragenic inversion of the mitochondrial DNA MTND1 gene causing fatal infantile lactic acidosis.</strong> Pediat. Res. 59: 440-444, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16492986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16492986</a>] [<a href="https://doi.org/10.1203/01.pdr.0000198771.78290.c4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16492986">Blakely et al. (2006)</a> noted that their findings illustrated the enormous phenotypic diversity that exists among pathogenic mtDNA mutations and reemphasized the need for appropriate genetic counseling for families affected by mtDNA disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10775530+16492986" 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">rs28616230 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28616230;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=rs28616230" 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=rs28616230" 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=RCV000010384 OR RCV002260596" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010384, RCV002260596" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010384...</a>
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<p>In 2 Korean families with LHON (<a href="/entry/535000">535000</a>), <a href="#32" class="mim-tip-reference" title="Kim, J. Y., Hwang, J.-M., Park, S. S. <strong>Mitochondrial DNA C4171A/ND1 is a novel primary causative mutation of Leber's hereditary optic neuropathy with a good prognosis.</strong> Ann. Neurol. 51: 630-634, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12112111/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12112111</a>] [<a href="https://doi.org/10.1002/ana.10177" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12112111">Kim et al. (2002)</a> identified a 4171C-A mutation in the MTND1 gene, resulting in a leu289-to-met substitution in a highly conserved region of an extramembrane loop. All 4 patients recovered spontaneously after suffering months to years following initial visual loss. The authors noted that the mutation does not alter the side-chain hydrophobicity, which they believed resulted in a good clinical prognosis because of the slight changes in the amino acid, and thus the protein, characteristics. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12112111" 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">rs28357970 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28357970;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=rs28357970" 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=rs28357970" 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=RCV000010382 OR RCV000853708 OR RCV000992363" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010382, RCV000853708, RCV000992363" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010382...</a>
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<p><a href="#57" class="mim-tip-reference" title="Simon, D. K., Friedman, J., Breakefield, X. O., Jankovic, J., Brin, M. F., Provias, J., Bressman, S. B., Charness, M. E., Tarsy, D., Johns, D. R., Tarnopolsky, M. A. <strong>A heteroplasmic mitochondrial complex I gene mutation in adult-onset dystonia.</strong> Neurogenetics 4: 199-205, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12756609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12756609</a>] [<a href="https://doi.org/10.1007/s10048-003-0150-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12756609">Simon et al. (2003)</a> identified a heteroplasmic 3796A-G transition in the MTND1 gene in a patient with adult-onset dystonia, spasticity, and core-type myopathy. The mutation resulted in conversion of a highly conserved threonine to an alanine. The same mutation was subsequently identified in 2 of 74 additional unrelated adult-onset dystonia patients. A muscle biopsy in 1 of these 2 patients showed abnormalities of electron transport chain activities. The mutation was absent in 64 patients with early-onset dystonia, 82 normal controls, and 65 patients with Parkinson disease (<a href="/entry/168600">168600</a>) or multiple system atrophy. Each of the 3 patients in whom <a href="#57" class="mim-tip-reference" title="Simon, D. K., Friedman, J., Breakefield, X. O., Jankovic, J., Brin, M. F., Provias, J., Bressman, S. B., Charness, M. E., Tarsy, D., Johns, D. R., Tarnopolsky, M. A. <strong>A heteroplasmic mitochondrial complex I gene mutation in adult-onset dystonia.</strong> Neurogenetics 4: 199-205, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12756609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12756609</a>] [<a href="https://doi.org/10.1007/s10048-003-0150-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12756609">Simon et al. (2003)</a> identified the 3796A-G mutation belonged to mitochondrial haplogroup H. They noted that <a href="#21" class="mim-tip-reference" title="Herrnstadt, C., Elson, J. L., Fahy, E., Preston, G., Turnbull, D. M., Anderson, C., Ghosh, S. S., Olefsky, J. M., Beal, M. F., Davis, R. E., Howell, N. <strong>Reduced-median-network analysis of complete mitochondrial DNA coding-region sequences for the major African, Asian, and European haplogroups.</strong> Am. J. Hum. Genet. 70: 1152-1171, 2002. Note: Erratum: Am. J. Hum. Genet. 71: 448 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11938495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11938495</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11938495[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/10.1086/339933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11938495">Herrnstadt et al. (2002)</a> had reported the 3796A-G mutation in 3 of 226 haplogroup H patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11938495+12756609" 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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LEBER OPTIC ATROPHY AND DYSTONIA, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199476122 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476122;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=rs199476122" 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=rs199476122" 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=RCV000010385 OR RCV000010386 OR RCV000056168 OR RCV002221474 OR RCV003298030" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010385, RCV000010386, RCV000056168, RCV002221474, RCV003298030" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010385...</a>
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<p><a href="#33" class="mim-tip-reference" title="Kirby, D. M., McFarland, R., Ohtake, A., Dunning, C., Ryan, M. T., Wilson, C., Ketteridge, D., Turnbull, D. M., Thorburn, D. R., Taylor, R. W. <strong>Mutations of the mitochondrial ND1 gene as a cause of MELAS.</strong> J. Med. Genet. 41: 784-789, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15466014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15466014</a>] [<a href="https://doi.org/10.1136/jmg.2004.020537" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15466014">Kirby et al. (2004)</a> described a patient with MELAS syndrome (<a href="/entry/540000">540000</a>) in whom the common 3243A-G mutation of the MTTL1 gene (<a href="/entry/590050#0001">590050.0001</a>) could not be detected, but who expressed a specific deficiency of complex I activity in both skeletal muscle and cultured fibroblasts; targeted sequencing of the mitochondrial tRNA and MTND genes identified a 3697G-A transition in the MTND1 gene, resulting in a gly131-to-ser (G131S) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15466014" 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="#58" class="mim-tip-reference" title="Spruijt, L., Smeets, H. J., Hendrickx, A., Bettink-Remeijer, M. W., Maat-Kievit, A., Schoonderwoerd, K. C., Sluiter, W., de Coo, I. F. <strong>Hintzen, R. Q.: A MELAS-associated ND1 mutation causing Leber hereditary optic neuropathy and spastic dystonia.</strong> Arch. Neurol. 64: 890-893, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17562939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17562939</a>] [<a href="https://doi.org/10.1001/archneur.64.6.890" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17562939">Spruijt et al. (2007)</a> reported a sister and brother with Leber optic atrophy and dystonia (<a href="/entry/500001">500001</a>). The 35-year-old sister developed sequential left and right vision loss, optic nerve atrophy, and bilateral central scotoma consistent with LHON. Serum and CSF lactate levels were increased. Her 34-year-old brother had developed progressive spastic dystonia beginning at age 3 years. Since age 27, he was wheelchair-bound with mental retardation, scoliosis, dysarthria, strabismus without ophthalmoplegia, and accumulation of abnormal mitochondria on sural nerve biopsy. His brain MRI showed bilateral hyperintensities in the putamen. Muscle biopsies from the sister and brother showed 8% and 16% residual complex I activity, respectively. Genetic analysis identified a heteroplasmic 3697G-A transition in the MTND1 gene. The mutation load was greater than 97% in muscle tissue of the woman with LHON and 88% in the blood of her brother. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17562939" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 MELAS SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199476123 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476123;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=rs199476123" 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=rs199476123" 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=RCV000010387 OR RCV000853718 OR RCV001542704" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010387, RCV000853718, RCV001542704" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010387...</a>
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<p><a href="#33" class="mim-tip-reference" title="Kirby, D. M., McFarland, R., Ohtake, A., Dunning, C., Ryan, M. T., Wilson, C., Ketteridge, D., Turnbull, D. M., Thorburn, D. R., Taylor, R. W. <strong>Mutations of the mitochondrial ND1 gene as a cause of MELAS.</strong> J. Med. Genet. 41: 784-789, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15466014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15466014</a>] [<a href="https://doi.org/10.1136/jmg.2004.020537" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15466014">Kirby et al. (2004)</a> described a patient with MELAS syndrome (<a href="/entry/540000">540000</a>) in whom the common 3243A-G mutation of the MTTL1 gene (<a href="/entry/590050#0001">590050.0001</a>) could not be detected, but who expressed a specific deficiency of complex I activity in both skeletal muscle and cultured fibroblasts; targeted sequencing of the mitochondrial tRNA and MTND genes identified a 3946G-A transition in the MTND1 gene, resulting in a glu214-to-lys (E214K) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15466014" 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">rs199476124 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476124;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=rs199476124" 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=rs199476124" 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=RCV000010388" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010388" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010388</a>
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<p><a href="#33" class="mim-tip-reference" title="Kirby, D. M., McFarland, R., Ohtake, A., Dunning, C., Ryan, M. T., Wilson, C., Ketteridge, D., Turnbull, D. M., Thorburn, D. R., Taylor, R. W. <strong>Mutations of the mitochondrial ND1 gene as a cause of MELAS.</strong> J. Med. Genet. 41: 784-789, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15466014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15466014</a>] [<a href="https://doi.org/10.1136/jmg.2004.020537" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15466014">Kirby et al. (2004)</a> described a patient with MELAS syndrome (<a href="/entry/540000">540000</a>) in whom the common 3243A-G mutation of the MTTL1 gene (<a href="/entry/590050#0001">590050.0001</a>) could not be detected, but who expressed a specific deficiency of complex I activity in both skeletal muscle and cultured fibroblasts; targeted sequencing of the mitochondrial tRNA and MTND genes identified a 3949T-C transition in the MTND1 gene, resulting in a tyr215-to-his (Y215H) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15466014" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0015 LEBER OPTIC ATROPHY</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199476125 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476125;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=rs199476125" 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=rs199476125" 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=RCV000010389 OR RCV002221475" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010389, RCV002221475" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010389...</a>
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<p>In 6 affected members of a large family and in an unrelated sporadic patient with Leber optic neuropathy (<a href="/entry/535000">535000</a>), <a href="#60" class="mim-tip-reference" title="Valentino, M. L., Barboni, P., Ghelli, A., Bucchi, L., Rengo, C., Achilli, A., Torroni, A., Lugaresi, A., Lodi, R., Barbiroli, B., Dotti, M. T., Federico, A., Baruzzi, A., Carelli, V. <strong>The ND1 gene of complex I is a mutational hot spot for Leber's hereditary optic neuropathy.</strong> Ann. Neurol. 56: 631-641, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15505787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15505787</a>] [<a href="https://doi.org/10.1002/ana.20236" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15505787">Valentino et al. (2004)</a> identified a 3733G-A transition in the MTND1 gene, resulting in a glu143-to-lys (E143K) substitution in a conserved part of an extramembrane loop facing the matrix side of the inner mitochondrial membrane. All affected individuals were homoplasmic for the mutation, with 100% mutant mtDNA in multiple tissue samples. Members of the large family showed a mild phenotype with some visual recovery in most patients. There was evidence of anticipation. Haplotype analysis indicated that the families did not share ancestry, suggesting that the mutation occurred twice independently. <a href="#60" class="mim-tip-reference" title="Valentino, M. L., Barboni, P., Ghelli, A., Bucchi, L., Rengo, C., Achilli, A., Torroni, A., Lugaresi, A., Lodi, R., Barbiroli, B., Dotti, M. T., Federico, A., Baruzzi, A., Carelli, V. <strong>The ND1 gene of complex I is a mutational hot spot for Leber's hereditary optic neuropathy.</strong> Ann. Neurol. 56: 631-641, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15505787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15505787</a>] [<a href="https://doi.org/10.1002/ana.20236" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15505787">Valentino et al. (2004)</a> noted that the 3733G-A mutation is near the common 3460A (<a href="#0001">516000.0001</a>) and 4171A (<a href="#0010">516000.0010</a>) LHON-associated mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15505787" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0016 DEAFNESS, NONSYNDROMIC SENSORINEURAL, MITOCHONDRIAL</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906730 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906730;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=rs387906730" 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=rs387906730" 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=RCV000022892 OR RCV000853648 OR RCV004713175 OR RCV004814917" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022892, RCV000853648, RCV004713175, RCV004814917" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022892...</a>
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<p>In affected members of a family with maternally inherited nonsyndromic mild sensorineural deafness (<a href="/entry/500008">500008</a>), <a href="#35" class="mim-tip-reference" title="Leveque, M., Marlin, S., Jonard, L., Procaccio, V., Reynier, P., Amati-Bonneau, P., Baulande, S., Pierron, D., Lacombe, D., Duriez, F., Francannet, C., Mom, T., and 13 others. <strong>Whole mitochondrial genome screening in maternally inherited non-syndromic hearing impairment using a microarray resequencing mitochondrial DNA chip.</strong> Europ. J. Hum. Genet. 15: 1145-1155, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17637808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17637808</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201891" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17637808">Leveque et al. (2007)</a> identified a homoplasmic 3388C-A transversion in the MTDN1 gene, which was identified by whole mitochondrial genome analysis. The variant was predicted to not be pathogenic. Affected individuals had congenital to early adult onset of mild hearing loss associated with tinnitus and benign paroxysmal positional vertigo. <a href="#20" class="mim-tip-reference" title="Gutierrez Cortes, N., Pertuiset, C., Dumon, E., Borlin, M., Hebert-Chatelain, E., Pierron, D., Feldmann, D., Jonard, L., Marlin, S., Letellier, T., Rocher, C. <strong>Novel mitochondrial DNA mutations responsible for maternally inherited nonsyndromic hearing loss.</strong> Hum. Mutat. 33: 681-689, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22241583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22241583</a>] [<a href="https://doi.org/10.1002/humu.22023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22241583">Gutierrez Cortes et al. (2012)</a> noted that the 3388C-A variant results in a leu28-to-met (L28M) substitution in a tyrosine-binding motif and a tyrosine kinase/phosphatase motif of the MTND1 protein. Cybrid cell lines carrying the mutation showed a 25% decline in mitochondrial oxygen consumption and a decrease of 55% in complex I activity compared to controls, indicating a defect in mitochondrial respiration. Complex I assembly, as assessed by gel electrophoresis, was also decreased (43% compared to controls), whereas other complexes were not affected. Reduced penetrance was observed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17637808+22241583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Attardi1983" class="mim-tip-reference" title="Attardi, G., Montoya, J. <strong>Analysis of human mitochondrial RNA..</strong> Methods Enzymol. 97: 435-469, 1983.">Attardi and Montoya (1983)</a>; <a href="#Brown1992" class="mim-tip-reference" title="Brown, M. D., Voljavec, A. S., Lott, M. T., Torroni, A., Yang, C.-C., Wallace, D. C. <strong>Mitochondrial DNA complex I and III mutations associated with Leber's hereditary optic neuropathy.</strong> Genetics 130: 163-173, 1992.">Brown et al. (1992)</a>; <a href="#Howell1991" class="mim-tip-reference" title="Howell, N., Kubacka, I., Xu, M., McCullough, D. A. <strong>Leber hereditary optic neuropathy: involvement of the mitochondrial ND1 gene and evidence for an intragenic suppressor mutation.</strong> Am. J. Hum. Genet. 48: 935-942, 1991.">Howell et al.
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(1991)</a>; <a href="#Johns1992" class="mim-tip-reference" title="Johns, D. R. <strong>Mitochondrial ND-1 mutation in Leber hereditary optic neuropathy.</strong> Am. J. Hum. Genet. 50: 872-874, 1992.">Johns et al. (1992)</a>; <a href="#Ragan1982" class="mim-tip-reference" title="Ragan, C. I., Galante, Y. M., Hatefi, Y. <strong>Purification of three iron-sulfur proteins from the iron-protein fragment of mitochondrial NADH-ubiquinone oxidoreductase.</strong> Biochemistry 21: 2518-2524, 1982.">Ragan et al. (1982)</a>
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[<a href="https://doi.org/10.1038/290457a0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00314729" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1634041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1634041</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1634041" 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/10.1096/fasebj.6.10.1634041" target="_blank">Full Text</a>]
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Brown, M. D., Voljavec, A. S., Lott, M. T., Torroni, A., Yang, C.-C., Wallace, D. C.
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<strong>Mitochondrial DNA complex I and III mutations associated with Leber's hereditary optic neuropathy.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1732158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1732158</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1732158" 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/genetics/130.1.163" target="_blank">Full Text</a>]
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[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://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6261411" 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/BF01544751" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.3764430" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.80.18.5535" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1042/bj2240525" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0003-9861(79)90126-7" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.77.11.6715" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.22023" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/339933" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2006.042168" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000265598.76172.59" 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.1992.01080230077025" target="_blank">Full Text</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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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 12/13/2018
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 4/16/2012<br>Cassandra L. Kniffin - updated : 10/19/2009<br>Cassandra L. Kniffin - updated : 4/4/2008<br>Cassandra L. Kniffin - updated : 11/30/2007<br>Cassandra L. Kniffin - updated : 12/12/2006<br>John Logan Black, III - updated : 7/20/2005<br>Cassandra L. Kniffin - updated : 6/28/2005<br>Victor A. McKusick - updated : 2/17/2005<br>Victor A. McKusick - updated : 10/13/2003<br>Cassandra L. Kniffin - updated : 12/11/2002<br>George E. Tiller - updated : 9/27/2002<br>Victor A. McKusick - updated : 8/20/2002<br>Victor A. McKusick - updated : 8/20/2002<br>Victor A. McKusick - updated : 1/10/2000<br>Victor A. McKusick - updated : 11/15/1999<br>Victor A. McKusick - updated : 6/15/1999<br>Douglas C. Wallace - updated : 4/6/1994
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</span>
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</div>
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Creation Date:
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<span class="mim-text-font">
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Victor A. McKusick : 3/2/1993
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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alopez : 08/11/2023
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carol : 02/22/2022<br>carol : 12/13/2018<br>carol : 07/08/2016<br>alopez : 12/19/2012<br>terry : 12/14/2012<br>terry : 7/6/2012<br>alopez : 4/23/2012<br>ckniffin : 4/16/2012<br>terry : 5/23/2011<br>terry : 11/3/2010<br>carol : 1/19/2010<br>wwang : 11/12/2009<br>ckniffin : 10/19/2009<br>terry : 8/26/2008<br>wwang : 4/15/2008<br>ckniffin : 4/4/2008<br>wwang : 12/7/2007<br>ckniffin : 11/30/2007<br>wwang : 12/18/2006<br>ckniffin : 12/12/2006<br>ckniffin : 8/29/2005<br>carol : 7/21/2005<br>terry : 7/20/2005<br>wwang : 7/14/2005<br>wwang : 7/13/2005<br>ckniffin : 6/28/2005<br>tkritzer : 2/24/2005<br>terry : 2/17/2005<br>mgross : 12/21/2004<br>terry : 12/21/2004<br>tkritzer : 10/24/2003<br>tkritzer : 10/14/2003<br>tkritzer : 10/13/2003<br>carol : 5/12/2003<br>carol : 12/12/2002<br>ckniffin : 12/11/2002<br>terry : 11/22/2002<br>cwells : 9/27/2002<br>tkritzer : 8/26/2002<br>tkritzer : 8/26/2002<br>terry : 8/20/2002<br>terry : 8/20/2002<br>terry : 1/19/2001<br>carol : 8/2/2000<br>terry : 7/25/2000<br>mgross : 1/10/2000<br>mgross : 11/30/1999<br>terry : 11/15/1999<br>jlewis : 6/17/1999<br>terry : 6/15/1999<br>dholmes : 4/17/1998<br>terry : 12/11/1997<br>terry : 7/10/1997<br>terry : 7/9/1997<br>terry : 1/21/1997<br>mark : 4/9/1996<br>mimman : 2/8/1996<br>mark : 6/22/1995<br>pfoster : 8/16/1994<br>jason : 6/17/1994<br>mimadm : 4/29/1994<br>carol : 3/8/1994
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<span class="mim-font">
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<strong>*</strong> 516000
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COMPLEX I, SUBUNIT ND1; MTND1
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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NADH-UBIQUINONE OXIDOREDUCTASE, SUBUNIT ND1<br />
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NADH DEHYDROGENASE, SUBUNIT 1
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<span class="mim-font">
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Other entities represented in this entry:
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<span class="h3 mim-font">
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MITOCHONDRIAL COMPLEX I DEFICIENCY, MITOCHONDRIAL TYPE 3, INCLUDED; MC1DM3, INCLUDED
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<strong><em>HGNC Approved Gene Symbol: MT-ND1</em></strong>
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<strong>SNOMEDCT:</strong> 26929004, 39925003, 49049000, 51178009, 58610003;
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<strong>ICD10CM:</strong> E88.41, G20, G20.A1, G30, G30.9, H47.22;
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<strong>ICD9CM:</strong> 331.0, 332, 332.0, 798.0;
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>Subunit 1 is one of 7 mitochondrial DNA (mtDNA) encoded subunits (MTND1, MTND2, MTND3, MTND4, MTND4L, 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). </p><p>Complex I is the first step in the electron transport chain of mitochondrial oxidative phosphorylation (OXPHOS) and is located within the mitochondrial inner membrane. It accepts electrons from NADH and transfers them, through a series of electron carriers, to ubiquinone (Coenzyme Q10). The internal electron carriers of complex I include flavin mononucleotide (FMN) and 6 iron-sulfur clusters designated N-1a, N-1b, N-2, N-3, N-4, and N-5 (Ohnishi, 1979; Ragan, 1987). Complex I can be subdivided into 3 main fractions: the flavoprotein fragment, the iron-protein fragment, and the hydrophobic protein fragment (Ragan, 1987). The flavoprotein fragment contains the FMN, 6 of the iron atoms, and 3 polypeptides (51, 24, and 10 kD) (Galante and Hatefi, 1979; Ragan et al., 1982). The NADH-binding site and FMN have been assigned to the 51-kD polypeptide (Chen and Guillory, 1981). The iron-protein fragment contains 9 or 10 iron atoms (Ragan et al., 1982), and a 15-kD protein from this fragment appears to be the ubiquinone-binding protein involved in electron transfer to ubiquinone (Suzuki and Ozawa, 1986). The MTND6 protein may also be located in the iron-protein fragment (Chomyn et al., 1986). The hydrophobic protein fragment contains the iron-sulfur centers that are the likely electron donors to ubiquinone (Ohnishi et al., 1985; Ohnishi et al., 1974). Of the 7 mitochondrial DNA Complex I genes, the gene products for MTND1, MTND3, and MTND4L have been localized to the hydrophobic protein fragment (Ragan, 1987), and the MTND2, MTND4, and MTND5 gene products probably reside there also. </p><p>The MTND1 polypeptide binds rotenone and rotenone analogs, and rotenone is thought to interact with the ubiquinone binding site. Hence, MTND1 might be involved in electron transfer to ubiquinone (Ragan, 1987; Earley and Ragan, 1984). However, studies on erythrosine-5-prime-iodoacetamide binding suggest that the rotenone and ubiquinone binding sites may not be identical (Ahmed and Krishnamoorthy, 1992). </p>
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<strong>Mapping</strong>
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<p>MTND1 is encoded by the guanine-rich heavy (H) strand of the mtDNA between nucleotide pairs (nps) 3307 and 4262 (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 MTND1 gene encompasses 955 nps of continuous coding sequence. It contains no introns, has a two-base (AC) 5-prime noncoding sequence, an ATA methionine start codon, and ends with the UA of the UAA termination codon (Anderson et al., 1981; Montoya et al., 1981; Ojala et al., 1981). It is transcribed as part of the polycistronic H-strand transcript, flanked by tRNALeuUUR and tRNAIle. The tRNAs fold within the transcript and are processed out freeing transcript 13, the MTND1 mRNA. This mRNA is then polyadenylated completing the termination codon (Anderson et al., 1981; Ojala et al., 1981; Attardi et al., 1982). </p>
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<strong>Gene Function</strong>
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<p>The predicted polypeptide has a molecular weight of 35.6 kD (Anderson et al., 1981; Wallace et al., 1994), but its apparent MW is 29.5 kD on SDS-polyacrylamide gels (PAGE) using Tris-glycine buffer (Oliver et al., 1984; Oliver and Wallace, 1982; Wallace et al., 1986) and 24 kD on SDS-PAGE using urea-phosphate buffer (Chomyn et al., 1983; Wallace et al., 1994). The amino terminal 17 amino acids have been shown in mouse to code for a polymorphic cell surface antigen (Loveland et al., 1990). </p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<p>Restriction site polymorphisms have been identified at the following nucleotide position for the indicated enzymes (where '+' = site gain, '-' = site loss relative to the reference sequence, Anderson et al., 1981): Alu I +3391, -3537, +3981; Dde I: +3388, -3534, +3846, +3930; Hae III: -3315, +3391, -3412, +3624, +3624/3833/9253, +3714/3744, +3744, +3842, -3849, +4092; Hha I: -3698; HincII: +3659, +3759; HinfI: +3359, +4092; Hpa I: +3592; Mbo I: -3569, +4026; Rsa I: -3337, +3371, +3397, +3987, +4051; Taq I: +3868, +3899, -3944 (Wallace et al., 1994). </p><p>Allelic variants of MTND1 have been reported in several disorders, including Leber hereditary optic neuropathy (LHON; 535000), Alzheimer disease (see 104300 and 502500), and Parkinson disease (PD; see 168600).</p><p>Opdal et al. (1999) reported point mutations in the MTND1 gene as a cause of sudden infant death syndrome (SIDS; 272120); see 516000.0008. </p><p>Munakata et al. (2004) examined the entire sequence of mtDNA in 6 subjects with bipolar disorder and comorbid somatic symptoms suggestive of mitochondrial disorders and identified several uncharacterized homoplastic nonsynonymous nucleotide substitutions. Of these, a 3644T-C mutation in the MTND1 gene was found in 5 of 199 patients with bipolar disorder (see 125480) but in none of 258 controls (p = 0.015). The 3644T-C mutation converts amino acid 113, valine, to alanine. Munakata et al. (2004) noted that val113 is well conserved from Drosophila to mammalian species. Using transmitochondrial cybrids, they found that the mutation decreased mitochondrial membrane potential and complex I activity compared to haplogroup-matched controls. Munakata et al. (2004) suggested that the mutation might increase the risk for bipolar disorder. </p>
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<h4>
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<span class="mim-font">
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<strong>Evolution</strong>
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<span class="mim-text-font">
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<p>Mitochondrial genomes exhibit a 20-fold range in protein gene content, from only 3 in the virtually extinct mtDNA of Plasmodium to 61 in Reclinomonas (Lang et al., 1999). However, even Reclinomonas mtDNA encodes only a small fraction of the proteins encoded by the bacterial progenitor of the mitochondrion. Adams et al. (2002) therefore suggested that the great majority of the original set of mitochondrial genes was either transferred to the nucleus or lost entirely from the cell early in eukaryotic evolution, before the emergence of essentially all extant lineages of eukaryotes. Mitochondrial gene loss and functional gene transfer to the nucleus essentially ceased in the common ancestor of animals, more than 600 million years ago, as the many sequenced animal mtDNAs all contain the same 13 protein-encoding genes. Although functional gene transfer has ceased in animals, pseudogenes of mitochondrial origin are common in animal nuclear genomes. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>16 Selected Examples):</strong>
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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 class="mim-text-font">
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MITOCHONDRIAL COMPLEX I DEFICIENCY, MITOCHONDRIAL TYPE 3, INCLUDED
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MTND1, LHON3460G-A
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<br />
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SNP: rs199476118,
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ClinVar: RCV000010370, RCV000143998, RCV000735416, RCV000757484, RCV003319165, RCV004814877
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<p />
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<p><strong><em>Leber Optic Atrophy</em></strong></p><p>
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The 3460G-A transition in the MTND1 gene converts the modestly conserved alanine 52 to a threonine (A52T). It is sufficient by itself to cause LHON (535000), is found in about 15% of Caucasian patients but not controls, has arisen on a variety of genetic backgrounds, can be heteroplasmic, results in vision loss in 14 to 40% of maternal relatives and 33 to 67% of males, and has a 22% visual recovery rate (Brown et al., 1992; Howell et al., 1991; Howell et al., 1992; Huoponen et al., 1991; Johns, 1992; Johns et al., 1992; Majander et al., 1991; Paulus et al., 1993) </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 (516003.0001), and the most severe LHON mutation, 3460. 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>Jaros et al. (2007) reported a 39-year-old woman with severe complicated LHON who developed progressive gait and sensory disturbances 5 years after onset of subacute bilateral visual failure. Visual symptoms included loss of acuity, central scotomata, optic atrophy, and nystagmus. She also had symmetric pyramidal-pattern lower limb weakness, hyperreflexia, and distal loss of vibratory sensation. Brain MRI showed symmetric high T2 signals in the substantia nigra, pons, and dorsal columns of the spinal cord. After an unexpected death, postmortem examination showed myelin loss and macrophage activation in the posterior columns of the upper spinal cord and neurodegeneration at multiple levels. Molecular analysis detected a homoplasmic 3460G-A mutation in blood and spinal cord. Her mtDNA haplotype H and HLA-DR8 status did not explain the severe phenotype. </p><p><strong><em>Mitochondrial Complex I Deficiency, Mitochondrial Type 3</em></strong></p><p>
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Hinttala et al. (2006) identified a homoplasmic 3460G-A mutation in skeletal muscle from an 18-year-old woman with severe mitochondrial complex I deficiency (MC1DM3) manifest as a progressive myopathy starting at age 10 years. She was wheelchair-bound with normal mental functioning. Her younger brother developed classic LHON. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 LEBER OPTIC ATROPHY</strong>
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</span>
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</h4>
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MTND1, LHON4160C
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<br />
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SNP: rs199476119,
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ClinVar: RCV000010372, RCV004595480
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<div>
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<span class="mim-text-font">
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<p>This allele converts the highly conserved leucine 285 to a proline (L285P). This mutation has been found in 1 large Australian pedigree manifesting LHON (535000) and additional neurological symptoms, together with the primary MTND6*LHON14484C. The mutation was homoplasmic in that pedigree in which 76% of the maternal relatives were affected, 54% of which were males (Howell et al., 1991). See also variant 516000.0006. </p>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 LEBER OPTIC ATROPHY</strong>
|
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</span>
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|
</h4>
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</div>
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<div>
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<span class="mim-text-font">
|
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NADH-DEHYDROGENASE SUBUNIT 1, MITOCHONDRIAL, MUTATION IN
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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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MTND1, LHON4216C
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<br />
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|
|
|
SNP: rs1599988,
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|
|
ClinVar: RCV000010373, RCV000709875, RCV000853749
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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>This allele changes the weakly conserved tyrosine at amino acid 304 to a histidine (Y304H) and is found in about 40% of the mtDNAs of European LHON (535000) patients. It has been found in association with 1 of 4 primary LHON mutations (MTND4*LHON11778A, MTND1*LHON3460A; MTND6*LHON14484A, and MTCYB*LHON15257A) as well as with the MTND5*LHON13708A and MTND2*LHON4917G secondary mutations. It is also found in 13% of the general population and hence is most likely a linked polymorphism (Brown et al., 1992; Johns and Berman, 1991) </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 LEBER OPTIC ATROPHY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MTND1, LHON3394C
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<br />
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SNP: rs41460449,
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ClinVar: RCV000010375, RCV000507319, RCV000853650, RCV004814878
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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>This mutation converts the highly conserved tyrosine at amino acid 30 to a histidine (Y30H). The mutation is rare among European LHON (535000) patients and found in about 0.9% of controls. It has only been observed on 1 haplotype and when combined with MTND6*LHON14484A is associated with blindness in 37% of maternal relatives, 100% of which are males. Patients with this genotype have an approximately 30% recovery rate (Brown et al., 1992; Johns et al., 1992; Obayashi et al., 1992) </p>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 ALZHEIMER DISEASE</strong>
|
|
</span>
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</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
|
|
PARKINSON DISEASE, INCLUDED
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|
</span>
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</div>
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<div>
|
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<span class="mim-text-font">
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MTND1, ADPD3397G
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|
<br />
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|
SNP: rs199476120,
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|
ClinVar: RCV000010376, RCV000010377, RCV000853653
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</span>
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</div>
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|
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<div>
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<span class="mim-text-font">
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|
<p>This allele converts the highly conserved methionine at amino acid 31 to a valine (M31V). It has been identified in 2 Caucasian pedigrees showing matrilineal transmission of Alzheimer disease (502500). One of these pedigrees also harbored the MTTQ*ADPD4336G mutation found in 5.2% of AD+PD (168600) patients but only in 0.4% of controls. The MTND1*ADPD3397G mutation was not found in 248 Caucasian controls, but was found in 1 Asian and in several members of the Ticuna Indian tribe of the Amazon (Shoffner et al., 1993). </p>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 LEBER OPTIC ATROPHY</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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MTND1, LHON4136G
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<br />
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|
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SNP: rs199476121,
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|
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ClinVar: RCV000010378, RCV000853739, RCV004713168
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|
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</span>
|
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>This allele converts the moderately conserved tyrosine at amino acid 277 to a cysteine (T277C). It was found in a sub-branch of the Australian LHON (535000) pedigree in association with mutations MTDN1*LHON4160C (516000.0002) and MTND6*14484C (516006.0001). This mutation has been proposed to ameliorate partially the symptoms of the latter (Howell et al., 1991). </p>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 COLORECTAL CANCER</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
SUDDEN INFANT DEATH SYNDROME, INCLUDED
|
|
</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
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|
MTND1, 3308T-C, MET1THR
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|
|
<br />
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|
|
SNP: rs28358582,
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|
|
ClinVar: RCV000010379, RCV000010380, RCV000239184, RCV000853627
|
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</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Early on, Warburg (1956) suggested that alterations of oxidative phosphorylation in tumor cells played a causative role in cancerous growth. Interest in the mitochondria with regard to neoplasia has revived, largely because of their role in apoptosis and other aspects of tumor biology. The mitochondrial genome is particularly susceptible to mutations because of the high level of reactive oxygen species (ROS) generated in this organelle, coupled with a low level of DNA repair. Polyak et al. (1998) analyzed the complete mtDNA genome of 10 human colorectal cancer (114500) cell lines by sequencing and found mutations in 7 (70%). The majority of mutations were transitions at purines, consistent with a ROS-related derivation. These mutations were somatic, and those evaluated occurred in the primary tumor from which the cell line was derived. Most of the mutations were homoplasmic, indicating that the mutant genome was dominant at the intracellular and intercellular levels. One of the mutations occurred in the MTND1 gene, a 3308T-C nucleotide substitution resulting in a met1-to-thr change in the MTND1 protein product. </p><p>Rocha et al. (1999) concluded that the 3308T-C mutation is an ancient marker of a common West African haplogroup. They found that all Iberian subjects with this mutation who were affected by mitochondrial encephalomyopathies harbored a particular mtDNA haplogroup. They pointed out that elimination of the methionine codon AUA at position 1 of the ND1 subunit is common in some human populations, suggesting that the maintenance of that codon is not critical in our species. Possibly this is because the third codon (AUG) of the human ND1 subunit also encodes for a methionine, and the ND1 subunit of the particular haplogroup observed in Iberian patients, although shortened by 2 amino acids, may still retain its functionality. </p><p>See 516000.0008 and Opdal et al. (1999) for evidence that the 3308T-C mutation can result in sudden infant death syndrome (SIDS; 272120). </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
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|
</div>
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</div>
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|
<div>
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 SUDDEN INFANT DEATH SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
MTND1, 3308T-G, MET1TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28358582,
|
|
|
|
|
|
|
|
ClinVar: RCV000010381, RCV000853629
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Opdal et al. (1999) investigated the MTTL1 gene (590050) and the first part of the MTND1 gene in 158 cases of sudden infant death syndrome (SIDS; 272120) and 97 controls. The basepairs in the range of 3230 to 3330 were investigated using PCR and temporal temperature gradient electrophoresis (TTGE). If a band shift was detected by TTGE, the area was investigated and the D-loop was sequenced. Three different point mutations (3290T-C in the MTTL1 gene (590050.0009), and 3308T-C (516000.0007) and 3308T-G in the MTND1 gene) were detected in 4 of the SIDS cases, while none of the controls was mutated. They also found a high D-loop substitution rate in these 4 cases. Opdal et al. (1999) suggested that the findings indicated that mtDNA mutations may play a role in some cases of SIDS. They pointed out that a 3250T-C mutation in the MTTL1 gene (590050.0008) had been detected in a family in which a sister of the proband and a maternal uncle died of SIDS, and that a 3303C-T mutation in the MTTL1 gene (590050.0004) had been detected in a family in which an older brother of the proband died of SIDS. The 3308T-G mutation of the MTND1 gene resulted in a met1-to-ter substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 MITOCHONDRIAL COMPLEX I DEFICIENCY, MITOCHONDRIAL TYPE 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MTND1, 7-BP INV
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000010383, RCV002260595
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Musumeci et al. (2000) studied a 43-year-old man, originally reported by Bet et al. (1990), who had complained, since childhood, of severe exercise intolerance and myalgia. Morphologic and biochemical studies of muscles showed 40% ragged-red fibers and an approximately 40% reduction of complex I activity consistent with complex I deficiency (MC1DM3). At age 43 years, he still complained of exercise intolerance; neurologic examination showed mild proximal limb weakness but was otherwise normal. His family history was noncontributory. The mother was alive and had always been a very active person. Neither of his 2 sibs complained of exercise intolerance. Musumeci et al. (2000) found an inversion of 7 nucleotides within the ND1 gene, which maintained the reading frame. The inversion, which altered 3 highly conserved amino acids in the polypeptide, was heteroplasmic in the patient's muscle but was not detectable in blood. This was said to be the first report of a pathogenic inversion mutation in human mtDNA. The inversion changed the normal amino acids 199-201 from asp-leu-ala to gly-lys-val. The 7-bp inverted segment was flanked by 8-bp inverted repeats. </p><p>Blakely et al. (2006) reported a female infant with the same 7-bp inversion in the MTND1 gene described by Musumeci et al. (2000). However, the infant had a much more severe phenotype and died at age 1 month with marked biventricular hypertrophy, aortic coarctation, and severe lactic acidosis. The mutation was present at high levels in several tissues including the heart (85%), muscle (84%), liver (87%), and cultured skin fibroblasts (70%). Complex I activity was estimated to be 24% of control values. There was no evidence of the mutation or respiratory complex I defect in a muscle biopsy from the patient's mother. Blakely et al. (2006) noted that their findings illustrated the enormous phenotypic diversity that exists among pathogenic mtDNA mutations and reemphasized the need for appropriate genetic counseling for families affected by mtDNA disease. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 LEBER OPTIC ATROPHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MTND1, LHON4171A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28616230,
|
|
|
|
|
|
|
|
ClinVar: RCV000010384, RCV002260596
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 Korean families with LHON (535000), Kim et al. (2002) identified a 4171C-A mutation in the MTND1 gene, resulting in a leu289-to-met substitution in a highly conserved region of an extramembrane loop. All 4 patients recovered spontaneously after suffering months to years following initial visual loss. The authors noted that the mutation does not alter the side-chain hydrophobicity, which they believed resulted in a good clinical prognosis because of the slight changes in the amino acid, and thus the protein, characteristics. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 DYSTONIA, ADULT-ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MTND1, 3796A-G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28357970,
|
|
|
|
|
|
|
|
ClinVar: RCV000010382, RCV000853708, RCV000992363
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Simon et al. (2003) identified a heteroplasmic 3796A-G transition in the MTND1 gene in a patient with adult-onset dystonia, spasticity, and core-type myopathy. The mutation resulted in conversion of a highly conserved threonine to an alanine. The same mutation was subsequently identified in 2 of 74 additional unrelated adult-onset dystonia patients. A muscle biopsy in 1 of these 2 patients showed abnormalities of electron transport chain activities. The mutation was absent in 64 patients with early-onset dystonia, 82 normal controls, and 65 patients with Parkinson disease (168600) or multiple system atrophy. Each of the 3 patients in whom Simon et al. (2003) identified the 3796A-G mutation belonged to mitochondrial haplogroup H. They noted that Herrnstadt et al. (2002) had reported the 3796A-G mutation in 3 of 226 haplogroup H patients. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
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|
<div>
|
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 MELAS SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
LEBER OPTIC ATROPHY AND DYSTONIA, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
MTND1, 3697G-A
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|
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<br />
|
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|
|
SNP: rs199476122,
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|
|
|
ClinVar: RCV000010385, RCV000010386, RCV000056168, RCV002221474, RCV003298030
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Kirby et al. (2004) described a patient with MELAS syndrome (540000) in whom the common 3243A-G mutation of the MTTL1 gene (590050.0001) could not be detected, but who expressed a specific deficiency of complex I activity in both skeletal muscle and cultured fibroblasts; targeted sequencing of the mitochondrial tRNA and MTND genes identified a 3697G-A transition in the MTND1 gene, resulting in a gly131-to-ser (G131S) substitution. </p><p>Spruijt et al. (2007) reported a sister and brother with Leber optic atrophy and dystonia (500001). The 35-year-old sister developed sequential left and right vision loss, optic nerve atrophy, and bilateral central scotoma consistent with LHON. Serum and CSF lactate levels were increased. Her 34-year-old brother had developed progressive spastic dystonia beginning at age 3 years. Since age 27, he was wheelchair-bound with mental retardation, scoliosis, dysarthria, strabismus without ophthalmoplegia, and accumulation of abnormal mitochondria on sural nerve biopsy. His brain MRI showed bilateral hyperintensities in the putamen. Muscle biopsies from the sister and brother showed 8% and 16% residual complex I activity, respectively. Genetic analysis identified a heteroplasmic 3697G-A transition in the MTND1 gene. The mutation load was greater than 97% in muscle tissue of the woman with LHON and 88% in the blood of her brother. </p>
|
|
</span>
|
|
</div>
|
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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<div>
|
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 MELAS SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
MTND1, 3946G-A
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|
|
<br />
|
|
|
|
SNP: rs199476123,
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|
|
|
|
ClinVar: RCV000010387, RCV000853718, RCV001542704
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Kirby et al. (2004) described a patient with MELAS syndrome (540000) in whom the common 3243A-G mutation of the MTTL1 gene (590050.0001) could not be detected, but who expressed a specific deficiency of complex I activity in both skeletal muscle and cultured fibroblasts; targeted sequencing of the mitochondrial tRNA and MTND genes identified a 3946G-A transition in the MTND1 gene, resulting in a glu214-to-lys (E214K) substitution. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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<div>
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 MELAS SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
MTND1, 3949T-C
|
|
|
|
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|
<br />
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SNP: rs199476124,
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ClinVar: RCV000010388
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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>Kirby et al. (2004) described a patient with MELAS syndrome (540000) in whom the common 3243A-G mutation of the MTTL1 gene (590050.0001) could not be detected, but who expressed a specific deficiency of complex I activity in both skeletal muscle and cultured fibroblasts; targeted sequencing of the mitochondrial tRNA and MTND genes identified a 3949T-C transition in the MTND1 gene, resulting in a tyr215-to-his (Y215H) substitution. </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>.0015 LEBER OPTIC ATROPHY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MTND1, LHON3733G-A
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<br />
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SNP: rs199476125,
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ClinVar: RCV000010389, RCV002221475
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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 6 affected members of a large family and in an unrelated sporadic patient with Leber optic neuropathy (535000), Valentino et al. (2004) identified a 3733G-A transition in the MTND1 gene, resulting in a glu143-to-lys (E143K) substitution in a conserved part of an extramembrane loop facing the matrix side of the inner mitochondrial membrane. All affected individuals were homoplasmic for the mutation, with 100% mutant mtDNA in multiple tissue samples. Members of the large family showed a mild phenotype with some visual recovery in most patients. There was evidence of anticipation. Haplotype analysis indicated that the families did not share ancestry, suggesting that the mutation occurred twice independently. Valentino et al. (2004) noted that the 3733G-A mutation is near the common 3460A (516000.0001) and 4171A (516000.0010) LHON-associated mutations. </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>.0016 DEAFNESS, NONSYNDROMIC SENSORINEURAL, MITOCHONDRIAL</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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MTND1, 3388C-A
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<br />
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SNP: rs387906730,
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ClinVar: RCV000022892, RCV000853648, RCV004713175, RCV004814917
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family with maternally inherited nonsyndromic mild sensorineural deafness (500008), Leveque et al. (2007) identified a homoplasmic 3388C-A transversion in the MTDN1 gene, which was identified by whole mitochondrial genome analysis. The variant was predicted to not be pathogenic. Affected individuals had congenital to early adult onset of mild hearing loss associated with tinnitus and benign paroxysmal positional vertigo. Gutierrez Cortes et al. (2012) noted that the 3388C-A variant results in a leu28-to-met (L28M) substitution in a tyrosine-binding motif and a tyrosine kinase/phosphatase motif of the MTND1 protein. Cybrid cell lines carrying the mutation showed a 25% decline in mitochondrial oxygen consumption and a decrease of 55% in complex I activity compared to controls, indicating a defect in mitochondrial respiration. Complex I assembly, as assessed by gel electrophoresis, was also decreased (43% compared to controls), whereas other complexes were not affected. Reduced penetrance was observed. </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">
|
|
Attardi and Montoya (1983); Brown et al. (1992); Howell et al.
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(1991); Johns et al. (1992); Ragan et al. (1982)
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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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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<strong>URF6, last unidentified reading frame of human mtDNA, codes for an NADH dehydrogenase subunit.</strong>
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Science 234: 614, 1986.
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Chomyn, A., Mariottini, P., Cleeter, M. W. J., Ragan, C. I., Matsuno-Yagi, A., Hatefi, Y., Doolittle, R. G., Attardi, G.
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<strong>Six unidentified reading frames of human mitochondrial DNA encode components of the respiratory-chain NADH dehydrogenase.</strong>
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Nature 314: 592-597, 1985.
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<strong>Identification of the polypeptides encoded in the ATPase 6 gene and in the unassigned reading frames 1 and 3 of human mtDNA.</strong>
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Earley, F. G., Ragan, C. I.
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Biochem. J. 224: 525-534, 1984.
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Galante, Y. M., Hatefi, Y.
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<p class="mim-text-font">
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Gutierrez Cortes, N., Pertuiset, C., Dumon, E., Borlin, M., Hebert-Chatelain, E., Pierron, D., Feldmann, D., Jonard, L., Marlin, S., Letellier, T., Rocher, C.
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</p>
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<p class="mim-text-font">
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Herrnstadt, C., Elson, J. L., Fahy, E., Preston, G., Turnbull, D. M., Anderson, C., Ghosh, S. S., Olefsky, J. M., Beal, M. F., Davis, R. E., Howell, N.
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<strong>Reduced-median-network analysis of complete mitochondrial DNA coding-region sequences for the major African, Asian, and European haplogroups.</strong>
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Am. J. Hum. Genet. 70: 1152-1171, 2002. Note: Erratum: Am. J. Hum. Genet. 71: 448 only, 2002.
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[PubMed: 11938495]
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[Full Text: https://doi.org/10.1086/339933]
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</p>
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<li>
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<p class="mim-text-font">
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Hinttala, R., Smeets, R., Moilanen, J. S., Ugalde, C., Uusimaa, J., Smeitink, J. A. M., Majamaa, K.
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<strong>Analysis of mitochondrial DNA sequences in patients with isolated or combined oxidative phosphorylation system deficiency. (Letter)</strong>
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[PubMed: 16738010]
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[Full Text: https://doi.org/10.1136/jmg.2006.042168]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Howell, N., Bindoff, L. A., McCullough, D. A., Kubacka, I., Poulton, J., Mackey, D., Taylor, L., Turnbull, D. M.
|
|
<strong>Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees.</strong>
|
|
Am. J. Hum. Genet. 49: 939-950, 1991.
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|
[PubMed: 1928099]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
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Howell, N., Kubacka, I., Xu, M., McCullough, D. A.
|
|
<strong>Leber hereditary optic neuropathy: involvement of the mitochondrial ND1 gene and evidence for an intragenic suppressor mutation.</strong>
|
|
Am. J. Hum. Genet. 48: 935-942, 1991.
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|
|
[PubMed: 2018041]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Howell, N., McCullough, D., Bodis-Wollner, I.
|
|
<strong>Molecular genetic analysis of a sporadic case of Leber hereditary optic neuropathy. (Letter)</strong>
|
|
Am. J. Hum. Genet. 50: 443-446, 1992.
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|
[PubMed: 1734726]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Huoponen, K., Vilkki, J., Aula, P., Nikoskelainen, E. K., Savontaus, M. L.
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Wallace, D. C., Yang, J., Ye, J., Lott, M. T., Oliver, N. A., McCarthy, J.
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Warburg, O.
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<strong>On the origin of cancer cells.</strong>
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Science 123: 309-314, 1956.
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[Full Text: https://doi.org/10.1126/science.123.3191.309]
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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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Cassandra L. Kniffin - updated : 12/13/2018<br>Cassandra L. Kniffin - updated : 4/16/2012<br>Cassandra L. Kniffin - updated : 10/19/2009<br>Cassandra L. Kniffin - updated : 4/4/2008<br>Cassandra L. Kniffin - updated : 11/30/2007<br>Cassandra L. Kniffin - updated : 12/12/2006<br>John Logan Black, III - updated : 7/20/2005<br>Cassandra L. Kniffin - updated : 6/28/2005<br>Victor A. McKusick - updated : 2/17/2005<br>Victor A. McKusick - updated : 10/13/2003<br>Cassandra L. Kniffin - updated : 12/11/2002<br>George E. Tiller - updated : 9/27/2002<br>Victor A. McKusick - updated : 8/20/2002<br>Victor A. McKusick - updated : 8/20/2002<br>Victor A. McKusick - updated : 1/10/2000<br>Victor A. McKusick - updated : 11/15/1999<br>Victor A. McKusick - updated : 6/15/1999<br>Douglas C. Wallace - updated : 4/6/1994
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Victor A. McKusick : 3/2/1993
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