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<title>
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Entry
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- *600438 - TRANSCRIPTION FACTOR A, MITOCHONDRIAL; TFAM
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- OMIM
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</ul>
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</nav>
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<div id="mimSearch" class="hidden-print">
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<div class="container">
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<form method="get" action="/search" id="mimEntrySearchForm" name="entrySearchForm" class="form-horizontal">
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchStart" name="start" value="1" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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<input type="hidden" id="mimSearchSort" name="sort" value="score desc, prefix_sort desc" />
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<div class="col-lg-8 col-md-8 col-sm-8 col-xs-8">
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<div class="form-group">
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<div class="input-group">
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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<div class="input-group-btn">
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<button type="submit" id="mimEntrySearchSubmit" class="btn btn-default" style="width: 5em;"><span class="glyphicon glyphicon-search"></span></button>
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<button type="button" class="btn btn-default dropdown-toggle" data-toggle="dropdown"> Options <span class="caret"></span></button>
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<ul class="dropdown-menu dropdown-menu-right">
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<li class="dropdown-header">
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Advanced Search
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/entry"> OMIM </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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<li role="separator" class="divider"></li>
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<a href="/history"> Search History </a>
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</form>
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<p />
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-2 hidden-sm hidden-xs">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*600438</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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</li>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/600438">Table View</a>
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</li>
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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>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
|
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
|
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
|
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<span class="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=ENSG00000108064;t=ENST00000487519" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=7019" 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=600438" 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="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=ENSG00000108064;t=ENST00000487519" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001270782,NM_003201,NR_073073,XM_011540121,XM_047425697" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_003201" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=600438" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
|
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</div>
|
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
|
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<span class="panel-title">
|
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=02702&isoform_id=02702_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/TFAM" 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/34799,417324,619859,4507401,47115243,54696184,54696186,74355508,116283599,116496711,119574556,119574557,119574558,119574559,119574560,161579137,189069117,197692183,197692433,311349578,311349580,311349582,311349584,311349586,311349588,311349590,311349592,311349594,311349596,311349598,311349600,311349602,311349604,311349606,311349608,311349610,311349612,311349614,311349616,311349618,311349620,311349622,311349624,311349626,311349628,311349630,311349632,311349634,311349636,311349638,311349640,311349642,311349644,311349646,311349648,311349650,311349652,311349654,311349656,399498566,767963675,2217278487,2462520832,2462520834" 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/Q00059" 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=7019" 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=ENSG00000108064;t=ENST00000487519" 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=TFAM" 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=TFAM" 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+7019" 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/TFAM" 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:7019" 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/7019" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr10&hgg_gene=ENST00000487519.6&hgg_start=58385410&hgg_end=58399220&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=600438[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=600438[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000108064" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=TFAM" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=TFAM" 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=TFAM" 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=TFAM&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/PA36458" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
|
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</div>
|
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</a>
|
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</span>
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</span>
|
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</div>
|
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:11741" 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/FBgn0038805.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:107810" 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/TFAM#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:107810" 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/7019/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=7019" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00001975;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-061013-552" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
|
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</div>
|
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
|
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</div>
|
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</a>
|
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</span>
|
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</span>
|
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</div>
|
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:7019" 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=TFAM&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
|
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
|
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
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600438
|
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</span>
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</span>
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</div>
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</div>
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<div>
|
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
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<span class="mim-font">
|
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TRANSCRIPTION FACTOR A, MITOCHONDRIAL; TFAM
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="alternativeTitles" class="mim-anchor"></a>
|
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<div>
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
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TCF6<br />
|
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TRANSCRIPTION FACTOR 6-LIKE 2; TCF6L2
|
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</span>
|
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</h4>
|
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</div>
|
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</div>
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<div>
|
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<br />
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</div>
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<div>
|
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<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">
|
|
Other entities represented in this entry:
|
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</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
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TRANSCRIPTION FACTOR 6-LIKE 1, INCLUDED; TCF6L1, INCLUDED
|
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</span>
|
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</div>
|
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<div>
|
|
<span class="h4 mim-font">
|
|
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|
TRANSCRIPTION FACTOR 6-LIKE 3, INCLUDED; TCF6L3, INCLUDED<br />
|
|
MITOCHONDRIAL TRANSCRIPTION FACTOR 1, INCLUDED; MTTF1, INCLUDED
|
|
</span>
|
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</div>
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</div>
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
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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">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=TFAM" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TFAM</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/10/214?start=-3&limit=10&highlight=214">10q21.1</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr10:58385410-58399220&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">10:58,385,410-58,399,220</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
|
</span>
|
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</p>
|
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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>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
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?Mitochondrial DNA depletion syndrome 15 (hepatocerebral type)
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<p>The TFAM gene encodes mitochondrial transcription factor A, which is essential for transcription, replication, and packaging of mtDNA into nucleoids, as well as critical for mitochondrial biogenesis (summary by <a href="#12" class="mim-tip-reference" title="Stiles, A. R., Simon, M. T., Stover, A., Eftekharian, S., Khanlou, N., Wang, H. L., Magaki, S., Lee, H., Partynski, K., Dorrani, N., Chang, R., Martinez-Agosto, J. A., Abdenur, J. E. <strong>Mutations in TFAM, encoding mitochondrial transcription factor A, cause neonatal liver failure associated with mtDNA depletion.</strong> Molec. Genet. Metab. 119: 91-99, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27448789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27448789</a>] [<a href="https://doi.org/10.1016/j.ymgme.2016.07.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27448789">Stiles et al., 2016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27448789" 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 mature TCF6 gene product, mitochondrial transcription factor A (TFAM; also known as mtTF1 or mtTFA), is a 162-amino acid protein that activates transcription of each mitochondrial DNA (mtDNA) strand by binding to an element of approximately 30 nucleotides present in both the light-strand and the heavy-strand promoters (<a href="#10" class="mim-tip-reference" title="Parisi, M. A., Clayton, D. A. <strong>Similarity of human mitochondrial transcription factor 1 to high mobility group proteins.</strong> Science 252: 965-969, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2035027/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2035027</a>] [<a href="https://doi.org/10.1126/science.2035027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2035027">Parisi and Clayton, 1991</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2035027" 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 transcription factor A is a key activator of mitochondrial transcription in mammals. It also has a role in mitochondrial DNA replication, since transcription generates an RNA primer necessary for initiation of mtDNA replication. In the mouse, testis-specific mtTFA transcripts encode a protein isoform that is imported to the nucleus, rather than into mitochondria, of spermatocytes and elongating spermatids. <a href="#6" class="mim-tip-reference" title="Larsson, N.-G., Oldfors, A., Garman, J. D., Barsh, G. S., Clayton, D. A. <strong>Down-regulation of mitochondrial transcription factor A during spermatogenesis in humans.</strong> Hum. Molec. Genet. 6: 185-191, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9063738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9063738</a>] [<a href="https://doi.org/10.1093/hmg/6.2.185" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9063738">Larsson et al. (1997)</a> reported molecular characterization of human mtTFA expression in somatic tissues and male germ cells. Similarly to the mouse, analysis of cDNAs and Northern blots identified abundant testis-specific transcript isoforms generated by use of alternate transcription initiation sites. However, unlike the mouse, none of the testis-specific transcripts predicted a nuclear protein isoform, and Western blot analysis identified only the mitochondrial form of mtTFA in human testis. Immunohistochemistry and in situ hybridization were used to compare the distribution of mtTFA protein, testis-specific mtTFA transcripts, mtDNA, and mtRNA in sections of human testis. Their results showed that mtTFA protein and mtDNA exhibit parallel gradients with high levels in undifferentiated male germ cells and low levels or an absence in differentiated male germ cells. Testis-specific transcripts exhibited the opposite pattern, suggesting to <a href="#6" class="mim-tip-reference" title="Larsson, N.-G., Oldfors, A., Garman, J. D., Barsh, G. S., Clayton, D. A. <strong>Down-regulation of mitochondrial transcription factor A during spermatogenesis in humans.</strong> Hum. Molec. Genet. 6: 185-191, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9063738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9063738</a>] [<a href="https://doi.org/10.1093/hmg/6.2.185" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9063738">Larsson et al. (1997)</a> that in both humans and mice, these testis-specific mtTFA transcripts downregulate mtTFA protein levels in mammalian mitochondria. Their findings demonstrated that mtTFA does not have a critical role in nucleus, suggested a mechanism for reducing mtDNA copy number during spermatogenesis, and had implications for the understanding of strictly maternal transmission of mtDNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9063738" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Mitochondrial nucleoids are large complexes containing, on average, 5 to 7 mtDNA genomes and several proteins involved in mtDNA replication and transcription, as well as related processes. <a href="#2" class="mim-tip-reference" title="Bogenhagen, D. F., Rousseau, D., Burke, S. <strong>The layered structure of human mitochondrial DNA nucleoids.</strong> J. Biol. Chem. 283: 3665-3675, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18063578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18063578</a>] [<a href="https://doi.org/10.1074/jbc.M708444200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18063578">Bogenhagen et al. (2008)</a> had previously shown that TFAM was associated with native purified HeLa cell nucleoids. Using a formaldehyde crosslinking technique, they found that TFAM copurified with mtDNA and was a core nucleoid protein. <a href="#2" class="mim-tip-reference" title="Bogenhagen, D. F., Rousseau, D., Burke, S. <strong>The layered structure of human mitochondrial DNA nucleoids.</strong> J. Biol. Chem. 283: 3665-3675, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18063578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18063578</a>] [<a href="https://doi.org/10.1074/jbc.M708444200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18063578">Bogenhagen et al. (2008)</a> confirmed these findings by Western blot analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18063578" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Yamamoto, H., Morino, K., Nishio, Y., Ugi, S., Yoshizaki, T., Kashiwagi, A., Maegawa, H. <strong>MicroRNA-494 regulates mitochondrial biogenesis in skeletal muscle through mitochondrial transcription factor A and forkhead box j3.</strong> Am. J. Physiol. Endocr. Metab. 303: E1419-E1427, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23047984/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23047984</a>] [<a href="https://doi.org/10.1152/ajpendo.00097.2012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23047984">Yamamoto et al. (2012)</a> observed upregulated expression of Foxj3 (<a href="/entry/616035">616035</a>) and mtTFA in differentiated mouse C2C12 myotubes, concomitant with downregulation of the regulatory microRNA Mir494 (<a href="/entry/616036">616036</a>). Knockdown and overexpression studies with Western blot, microarray, and reporter gene analyses showed that Mir494 downregulated translation of Foxj3 and mtTFA mRNAs in proliferating C2C12 myoblasts by binding to conserved target sequences in their 3-prime UTRs. Mir494 did not cause mRNA degradation. Endurance exercise in mice stimulated mitochondrial biogenesis in skeletal muscle, concomitant with decreased expression of Mir494 and elevated expression of Foxj3 and mtTFA. <a href="#17" class="mim-tip-reference" title="Yamamoto, H., Morino, K., Nishio, Y., Ugi, S., Yoshizaki, T., Kashiwagi, A., Maegawa, H. <strong>MicroRNA-494 regulates mitochondrial biogenesis in skeletal muscle through mitochondrial transcription factor A and forkhead box j3.</strong> Am. J. Physiol. Endocr. Metab. 303: E1419-E1427, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23047984/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23047984</a>] [<a href="https://doi.org/10.1152/ajpendo.00097.2012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23047984">Yamamoto et al. (2012)</a> concluded that FOXJ3 and mtTFA promote mitochondrial biogenesis and that MIR494 inhibits their expression and activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23047984" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="West, A. P., Khoury-Hanold, W., Staron, M., Tal, M. C., Pineda, C. M., Lang, S. M., Bestwick, M., Duguay, B. A., Raimundo, N., MacDuff, D. A., Kaech, S. M., Smiley, J. R., Means, R. E., Iwasaki, A., Shadel, G. S. <strong>Mitochondrial DNA stress primes the antiviral innate immune response.</strong> Nature 520: 553-557, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25642965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25642965</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25642965[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature14156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25642965">West et al. (2015)</a> showed that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signaling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, the authors found that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (<a href="/entry/613973">613973</a>) and promotes STING (<a href="/entry/612374">612374</a>)/IRF3 (<a href="/entry/603734">603734</a>)-dependent signaling to elevate interferon-stimulated gene expression, potentiate type I interferon responses, and confer broad viral resistance. Furthermore, <a href="#16" class="mim-tip-reference" title="West, A. P., Khoury-Hanold, W., Staron, M., Tal, M. C., Pineda, C. M., Lang, S. M., Bestwick, M., Duguay, B. A., Raimundo, N., MacDuff, D. A., Kaech, S. M., Smiley, J. R., Means, R. E., Iwasaki, A., Shadel, G. S. <strong>Mitochondrial DNA stress primes the antiviral innate immune response.</strong> Nature 520: 553-557, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25642965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25642965</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25642965[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature14156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25642965">West et al. (2015)</a> demonstrated that herpes viruses induce mtDNA stress, which enhances antiviral signaling and type I interferon responses during infection. <a href="#16" class="mim-tip-reference" title="West, A. P., Khoury-Hanold, W., Staron, M., Tal, M. C., Pineda, C. M., Lang, S. M., Bestwick, M., Duguay, B. A., Raimundo, N., MacDuff, D. A., Kaech, S. M., Smiley, J. R., Means, R. E., Iwasaki, A., Shadel, G. S. <strong>Mitochondrial DNA stress primes the antiviral innate immune response.</strong> Nature 520: 553-557, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25642965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25642965</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25642965[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature14156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25642965">West et al. (2015)</a> concluded that their results further demonstrated that mitochondria are central participants in innate immunity, identified mtDNA stress as a cell-intrinsic trigger of antiviral signaling, and suggested that cellular monitoring of mtDNA homeostasis cooperates with canonical virus-sensing mechanisms to fully engage antiviral innate immunity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25642965" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By Southern blot analysis of restriction enzyme digests of human/Chinese hamster somatic cell hybrid lines, <a href="#9" class="mim-tip-reference" title="Milatovich, A., Parisi, M. A., Poulton, J., Clayton, D. A., Francke, U. <strong>Sequences homologous to MTTF1, mitochondrial transcription factor 1, are located on human chromosomes 7 (7pter-cen), 10 and 11 (11cen-qter). (Abstract)</strong> Cytogenet. Cell Genet. 58: 1924 only, 1992."None>Milatovich et al. (1992)</a> mapped TFAM sequences, which they called MTTF1, to 3 different chromosomes: chromosomes 10, 7p, and 11q.</p><p>By PCR-based screening of a somatic cell hybrid panel and by fluorescence in situ hybridization, <a href="#13" class="mim-tip-reference" title="Tiranti, V., Rossi, E., Ruiz-Carrillo, A., Rossi, G., Rocchi, M., DiDonato, S., Zuffardi, O., Zeviani, M. <strong>Chromosomal localization of mitochondrial transcription factor A (TCF6), single-stranded DNA-binding protein (SSBP), and endonuclease G (ENDOG), three human housekeeping genes involved in mitochondrial biogenesis.</strong> Genomics 25: 559-564, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7789991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7789991</a>] [<a href="https://doi.org/10.1016/0888-7543(95)80058-t" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7789991">Tiranti et al. (1995)</a> assigned the TFAM gene to 10q21. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7789991" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Scott, A. F. <strong>Personal Communication.</strong> Baltimore, Md. 9/20/2007."None>Scott (2007)</a> stated that the sequences mapped to chromosomes 7p (TCF6L1) and 11q (MTTF1, or TCF6L3) are pseudogenes.</p><p><a href="#5" class="mim-tip-reference" title="Larsson, N.-G., Barsh, G. S., Clayton, D. A. <strong>Structure and chromosomal localization of the mouse mitochondrial transcription factor A gene (Tfam).</strong> Mammalian Genome 8: 139-140, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9060414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9060414</a>] [<a href="https://doi.org/10.1007/s003359900373" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9060414">Larsson et al. (1997)</a> mapped the mouse mitochondrial transcription factor A gene (Tfam) to the central part of mouse chromosome 10. This region exhibits syntenic homology with human 10q21. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9060414" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 sibs, born of consanguineous parents of Colombian-Basque descent, with mitochondrial DNA depletion syndrome-15 (MTDPS15; <a href="/entry/617156">617156</a>), <a href="#12" class="mim-tip-reference" title="Stiles, A. R., Simon, M. T., Stover, A., Eftekharian, S., Khanlou, N., Wang, H. L., Magaki, S., Lee, H., Partynski, K., Dorrani, N., Chang, R., Martinez-Agosto, J. A., Abdenur, J. E. <strong>Mutations in TFAM, encoding mitochondrial transcription factor A, cause neonatal liver failure associated with mtDNA depletion.</strong> Molec. Genet. Metab. 119: 91-99, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27448789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27448789</a>] [<a href="https://doi.org/10.1016/j.ymgme.2016.07.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27448789">Stiles et al. (2016)</a> identified a homozygous missense mutation in the TFAM gene (P178L; <a href="#0001">600438.0001</a>). The mutation, which was found by exome sequencing, segregated with the disorder in the family. Patient fibroblasts showed increased TFAM mRNA but decreased protein levels, consistent with a compensatory mechanism. Patient fibroblasts also had decreased mtDNA copy number, decreased basal respiration, decreased number of nucleoids, and presence of abnormal nucleoid aggregates compared to controls, all indicative of mitochondrial dysfunction. The patients had neonatal onset of rapidly progressive liver failure, resulting in death in infancy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27448789" 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 regulation of mitochondrial DNA expression is crucial for mitochondrial biogenesis during development and differentiation. <a href="#7" class="mim-tip-reference" title="Larsson, N.-G., Wang, J., Wilhelmsson, H., Oldfors, A., Rustin, P., Lewandoski, M., Barsh, G. S., Clayton, D. A. <strong>Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice.</strong> Nature Genet. 18: 231-236, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9500544/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9500544</a>] [<a href="https://doi.org/10.1038/ng0398-231" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9500544">Larsson et al. (1998)</a> disrupted the mouse Tfam gene by gene targeting. Heterozygous mice exhibited reduced mtDNA copy number and respiratory chain deficiency in heart. Homozygous knockout embryos exhibited a severe mtDNA depletion with abolished oxidative phosphorylation. Mutant embryos proceed through implantation and gastrulation, but die before embryonic day (E)10.5. Thus, Tfam is the first mammalian protein demonstrated to regulate mtDNA copy number in vivo and is essential for mitochondrial biogenesis and embryonic development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9500544" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Wang, J., Wilhelmsson, H., Graff, C., Li, H., Oldfors, A., Rustin, P., Bruning, J. C., Kahn, C. R., Clayton, D. A., Barsh, G. S., Thoren, P., Larsson, N.-G. <strong>Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression.</strong> Nature Genet. 21: 133-137, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9916807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9916807</a>] [<a href="https://doi.org/10.1038/5089" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9916807">Wang et al. (1999)</a> reported that hallmarks of mtDNA mutation disorders can be reproduced in the mouse using a conditional mutation strategy to manipulate the expression of the gene encoding mitochondrial transcription factor A (Tfam), which regulates transcription and replication of mtDNA. Using a loxP-flanked Tfam allele in combination with a cre-recombinase transgene under control of the muscle creatine kinase promoter, they disrupted Tfam in heart and muscle. Mutant animals developed a mosaic cardiac-specific progressive respiratory chain deficiency, dilated cardiomyopathy, and atrioventricular heart conduction blocks, and died at 2 to 4 weeks of age. This animal model reproduced biochemical, morphologic, and physiologic features of the dilated cardiomyopathy of Kearns-Sayre syndrome (<a href="/entry/530000">530000</a>). The findings provided genetic evidence that the respiratory chain is critical for normal heart function. The method should make it possible to disrupt oxidative phosphorylation in virtually any organ of the mouse by expressing cre-recombinase in a tissue-specific manner. This system might shed light on the role of oxidative phosphorylation in aging and in the pathogenesis of common human disorders such as heart failure, diabetes mellitus, and neurodegenerative diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9916807" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Li, H., Wang, J., Wilhelmsson, H., Hansson, A., Thoren, P., Duffy, J., Rustin, P., Larsson, N.-G. <strong>Genetic modification of survival in tissue-specific knockout mice with mitochondrial cardiomyopathy.</strong> Proc. Nat. Acad. Sci. 97: 3467-3472, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10737799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10737799</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10737799[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.97.7.3467" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10737799">Li et al. (2000)</a> described a heart-knockout strain obtained by mating Tfam(loxP) mice to animals expressing cre-recombinase from the alpha-myosin heavy chain (Myhca; <a href="/entry/160710">160710</a>) promoter. This promoter is active from embryonic day 8, and the knockouts had onset of mitochondrial cardiomyopathy during embryogenesis. The age of onset of cardiac respiratory chain dysfunction could thus be controlled by temporal regulation of cre-recombinase expression. Approximately 75% of the knockouts died in the neonatal period, whereas, surprisingly, approximately 25% survived for several months before dying from dilated cardiomyopathy with atrioventricular heart conduction blocks. Modifying genes affect the life span of knockouts, because approximately 95% of the knockout offspring from an intercross of the longer-living knockouts survived the neonatal period. Thus, the tissue-specific knockouts described by <a href="#8" class="mim-tip-reference" title="Li, H., Wang, J., Wilhelmsson, H., Hansson, A., Thoren, P., Duffy, J., Rustin, P., Larsson, N.-G. <strong>Genetic modification of survival in tissue-specific knockout mice with mitochondrial cardiomyopathy.</strong> Proc. Nat. Acad. Sci. 97: 3467-3472, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10737799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10737799</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10737799[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.97.7.3467" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10737799">Li et al. (2000)</a> not only reproduced important pathophysiologic features of mitochondrial cardiomyopathy but also provided a powerful system by which to identify modifying genes of potential therapeutic value. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10737799" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Ekstrand, M. I., Falkenberg, M., Rantanen, A., Park, C. B., Gaspari,P M., Hultenby, K., Rustin, P., Gustafsson, C. M., Larsson, N.-G. <strong>Mitochondrial transcription factor A regulates mtDNA copy number in mammals.</strong> Hum. Molec. Genet. 13: 935-944, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15016765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15016765</a>] [<a href="https://doi.org/10.1093/hmg/ddh109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15016765">Ekstrand et al. (2004)</a> generated PAC transgenic mice ubiquitously expressing human TFAM. Expression of the human TFAM protein in the mouse did not result in downregulation of endogenous Tfam expression, thus resulting in a general increase of mtDNA copy number. Using a combination of mice with TFAM overexpression and TFAM knockout, the authors demonstrated that mtDNA copy number is directly proportional to the total TFAM protein levels. The expression of human TFAM in the mouse resulted in upregulation of mtDNA copy number without increasing respiratory chain capacity or mitochondrial mass. The authors proposed a novel role for TFAM in direct regulation of mtDNA copy number in mammals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15016765" 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="#1" class="mim-tip-reference" title="Aydin, J., Andersson, D. C., Hanninen, S. L., Wredenberg, A., Tavi, P., Park, C. B., Larsson, N.-G., Bruton, J. D., Westerblad, H. <strong>Increased mitochondrial Ca2+ and decreased sarcoplasmic reticulum Ca2+ in mitochondrial myopathy.</strong> Hum. Molec. Genet. 18: 278-288, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18945718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18945718</a>] [<a href="https://doi.org/10.1093/hmg/ddn355" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18945718">Aydin et al. (2009)</a> used mice with skeletal muscle-specific disruption of Tfam to study whether change in cellular Ca2+ handling is part of the mechanism of muscle dysfunction in mitochondrial myopathy. Muscles of Tfam knockout mice show a progressive deterioration in respiratory chain function over their approximately 4-month life span. Force measurements were combined with measurements of cytosolic Ca2+, mitochondrial Ca2+, and membrane potential and reactive oxygen species in intact adult muscle fibers. There was reduced sarcoplasmic reticulum Ca2+ storage capacity in Tfam knockout muscles due to a decreased expression of calsequestrin-1 (CASQ1; <a href="/entry/114250">114250</a>). There were no signs of oxidative stress in Tfam knockout cells, whereas they displayed increased mitochondrial Ca2+ levels during repeated contractions. Mitochondrial Ca2+ levels remained elevated long after the end of stimulation in muscle cells from Tfam knockout mice, and the increase was smaller in the presence of the cyclophilin D (<a href="/entry/601753">601753</a>)-binding inhibitor cyclosporin A. The mitochondrial membrane potential in Tfam knockout cells did not decrease during repeated contractions. The authors suggested that the observed changes in Ca2+ handling may be adaptive responses with long-term detrimental effects. Reduced sarcoplasmic reticulum Ca2+ release may decrease ATP expenditure, but it also induces muscle weakness. Increased Ca2+ levels in the mitochondrial matrix may stimulate mitochondrial metabolism acutely, but may also trigger cell damage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18945718" 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="#3" class="mim-tip-reference" title="Desdin-Mico, G., Soto-Heredero, G., Aranda, J. F., Oller, J., Carrasco, E., Gabande-Rodriguez, E., Blanco, E. M., Alfranca, A., Cusso, L., Desco, M., Ibanez, B., Gortazar, A. R., Fernandez-Marcos, P., Navarro, M. N., Hernaez, B., Alcami, A., Baixauli, F., Mittelbrunn, M. <strong>T cells with dysfunctional mitochondria induce multimorbidity and premature senescence.</strong> Science 368: 1371-1376, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32439659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32439659</a>] [<a href="https://doi.org/10.1126/science.aax0860" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32439659">Desdin-Mico et al. (2020)</a> found that mice with T cell-specific deletion of Tfam had T cells with dysfunctional mitochondria that acted as accelerators of senescence. These cells instigated multiple aging-related features in mutant mice, including metabolic, cognitive, physical, and cardiovascular alterations, that resulted in premature death. T-cell metabolic failure induced accumulation of circulating cytokines, resembling chronic inflammation characteristic of aging, and this cytokine storm acted as a systemic inducer of senescence. Blocking Tnf (<a href="/entry/191160">191160</a>) signaling or preventing senescence with nicotinamide adenine dinucleotide precursors partially rescued premature aging in mutant mice. <a href="#3" class="mim-tip-reference" title="Desdin-Mico, G., Soto-Heredero, G., Aranda, J. F., Oller, J., Carrasco, E., Gabande-Rodriguez, E., Blanco, E. M., Alfranca, A., Cusso, L., Desco, M., Ibanez, B., Gortazar, A. R., Fernandez-Marcos, P., Navarro, M. N., Hernaez, B., Alcami, A., Baixauli, F., Mittelbrunn, M. <strong>T cells with dysfunctional mitochondria induce multimorbidity and premature senescence.</strong> Science 368: 1371-1376, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32439659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32439659</a>] [<a href="https://doi.org/10.1126/science.aax0860" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32439659">Desdin-Mico et al. (2020)</a> concluded that T cells can regulate organismal fitness and life span, highlighting the importance of tight immunometabolic control in both aging and the onset of age-associated diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32439659" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 sibs, born of consanguineous parents of Colombian-Basque descent, with mitochondrial DNA depletion syndrome-15 (MTDPS15; <a href="/entry/617156">617156</a>), <a href="#12" class="mim-tip-reference" title="Stiles, A. R., Simon, M. T., Stover, A., Eftekharian, S., Khanlou, N., Wang, H. L., Magaki, S., Lee, H., Partynski, K., Dorrani, N., Chang, R., Martinez-Agosto, J. A., Abdenur, J. E. <strong>Mutations in TFAM, encoding mitochondrial transcription factor A, cause neonatal liver failure associated with mtDNA depletion.</strong> Molec. Genet. Metab. 119: 91-99, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27448789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27448789</a>] [<a href="https://doi.org/10.1016/j.ymgme.2016.07.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27448789">Stiles et al. (2016)</a> identified a homozygous c.533C-T transition (c.533C-T, NM_003201.2) in the TFAM gene, resulting in a pro178-to-leu (P178L) substitution in the HMG box B domain, which is involved in mtDNA binding and compaction. The mutation was predicted to result in steric hindrance and decreased binding ability of TFAM to mtDNA. The mutation, which was found by exome sequencing, segregated with the disorder in the family, and was found in 2 of 118,504 chromosomes in the ExAC database. Patient fibroblasts showed increased TFAM mRNA but decreased protein levels, consistent with a compensatory mechanism. Patient cells also had decreased mtDNA copy number, decreased basal respiration, decreased number of nucleoids, and presence of abnormal nucleoid aggregates compared to controls. The patients had neonatal onset of rapidly progressive liver failure, resulting in death in infancy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27448789" 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="#Tominaga1992" class="mim-tip-reference" title="Tominaga, K., Akiyama, S., Kagawa, Y., Ohta, S. <strong>Upstream region of a genomic gene for human mitochondrial transcription factor 1.</strong> Biochim. Biophys. Acta 1131: 217-219, 1992.">Tominaga et al. (1992)</a>
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Stiles, A. R., Simon, M. T., Stover, A., Eftekharian, S., Khanlou, N., Wang, H. L., Magaki, S., Lee, H., Partynski, K., Dorrani, N., Chang, R., Martinez-Agosto, J. A., Abdenur, J. E.
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<strong>Mutations in TFAM, encoding mitochondrial transcription factor A, cause neonatal liver failure associated with mtDNA depletion.</strong>
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Molec. Genet. Metab. 119: 91-99, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27448789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27448789</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27448789" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ymgme.2016.07.001" target="_blank">Full Text</a>]
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Tominaga, K., Akiyama, S., Kagawa, Y., Ohta, S.
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<strong>Upstream region of a genomic gene for human mitochondrial transcription factor 1.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1610904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1610904</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1610904" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9916807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9916807</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9916807" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/5089" target="_blank">Full Text</a>]
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<a id="West2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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West, A. P., Khoury-Hanold, W., Staron, M., Tal, M. C., Pineda, C. M., Lang, S. M., Bestwick, M., Duguay, B. A., Raimundo, N., MacDuff, D. A., Kaech, S. M., Smiley, J. R., Means, R. E., Iwasaki, A., Shadel, G. S.
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<strong>Mitochondrial DNA stress primes the antiviral innate immune response.</strong>
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Nature 520: 553-557, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25642965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25642965</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25642965[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25642965" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature14156" target="_blank">Full Text</a>]
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<a id="Yamamoto2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yamamoto, H., Morino, K., Nishio, Y., Ugi, S., Yoshizaki, T., Kashiwagi, A., Maegawa, H.
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<strong>MicroRNA-494 regulates mitochondrial biogenesis in skeletal muscle through mitochondrial transcription factor A and forkhead box j3.</strong>
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Am. J. Physiol. Endocr. Metab. 303: E1419-E1427, 2012. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23047984/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23047984</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23047984" 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/10.1152/ajpendo.00097.2012" target="_blank">Full Text</a>]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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Ada Hamosh - updated : 10/20/2020
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Cassandra L. Kniffin - updated : 10/13/2016<br>Ada Hamosh - updated : 06/26/2015<br>Patricia A. Hartz - updated : 9/26/2014<br>George E. Tiller - updated : 4/17/2009<br>Patricia A. Hartz - updated : 9/24/2008<br>George E. Tiller - updated : 9/18/2006<br>Victor A. McKusick - updated : 4/20/2000<br>Victor A. McKusick - updated : 12/29/1998<br>Victor A. McKusick - updated : 2/27/1998<br>Victor A. McKusick - updated : 4/15/1997<br>Victor A. McKusick - updated : 4/4/1997
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Creation Date:
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<span class="mim-text-font">
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Victor A. McKusick : 3/6/1995
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mgross : 10/20/2020
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carol : 06/04/2019<br>alopez : 10/17/2016<br>ckniffin : 10/13/2016<br>alopez : 06/26/2015<br>carol : 10/1/2014<br>mgross : 9/30/2014<br>mcolton : 9/26/2014<br>alopez : 4/17/2009<br>mgross : 9/25/2008<br>terry : 9/24/2008<br>carol : 9/20/2007<br>alopez : 9/18/2006<br>carol : 8/1/2005<br>terry : 4/20/2000<br>carol : 12/29/1998<br>alopez : 12/21/1998<br>alopez : 2/27/1998<br>terry : 2/27/1998<br>jenny : 4/15/1997<br>terry : 4/4/1997<br>jenny : 4/4/1997<br>terry : 4/2/1997<br>jamie : 2/5/1997<br>carol : 3/7/1995<br>carol : 3/6/1995
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<strong>*</strong> 600438
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TRANSCRIPTION FACTOR A, MITOCHONDRIAL; TFAM
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<em>Alternative titles; symbols</em>
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TCF6<br />
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TRANSCRIPTION FACTOR 6-LIKE 2; TCF6L2
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Other entities represented in this entry:
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TRANSCRIPTION FACTOR 6-LIKE 1, INCLUDED; TCF6L1, INCLUDED
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TRANSCRIPTION FACTOR 6-LIKE 3, INCLUDED; TCF6L3, INCLUDED<br />
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MITOCHONDRIAL TRANSCRIPTION FACTOR 1, INCLUDED; MTTF1, INCLUDED
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<strong><em>HGNC Approved Gene Symbol: TFAM</em></strong>
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Cytogenetic location: 10q21.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 10:58,385,410-58,399,220 </span>
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</em>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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10q21.1
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<span class="mim-font">
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?Mitochondrial DNA depletion syndrome 15 (hepatocerebral type)
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<span class="mim-font">
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617156
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Autosomal recessive
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>The TFAM gene encodes mitochondrial transcription factor A, which is essential for transcription, replication, and packaging of mtDNA into nucleoids, as well as critical for mitochondrial biogenesis (summary by Stiles et al., 2016). </p>
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<strong>Cloning and Expression</strong>
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<p>The mature TCF6 gene product, mitochondrial transcription factor A (TFAM; also known as mtTF1 or mtTFA), is a 162-amino acid protein that activates transcription of each mitochondrial DNA (mtDNA) strand by binding to an element of approximately 30 nucleotides present in both the light-strand and the heavy-strand promoters (Parisi and Clayton, 1991). </p>
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<strong>Gene Function</strong>
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<p>Mitochondrial transcription factor A is a key activator of mitochondrial transcription in mammals. It also has a role in mitochondrial DNA replication, since transcription generates an RNA primer necessary for initiation of mtDNA replication. In the mouse, testis-specific mtTFA transcripts encode a protein isoform that is imported to the nucleus, rather than into mitochondria, of spermatocytes and elongating spermatids. Larsson et al. (1997) reported molecular characterization of human mtTFA expression in somatic tissues and male germ cells. Similarly to the mouse, analysis of cDNAs and Northern blots identified abundant testis-specific transcript isoforms generated by use of alternate transcription initiation sites. However, unlike the mouse, none of the testis-specific transcripts predicted a nuclear protein isoform, and Western blot analysis identified only the mitochondrial form of mtTFA in human testis. Immunohistochemistry and in situ hybridization were used to compare the distribution of mtTFA protein, testis-specific mtTFA transcripts, mtDNA, and mtRNA in sections of human testis. Their results showed that mtTFA protein and mtDNA exhibit parallel gradients with high levels in undifferentiated male germ cells and low levels or an absence in differentiated male germ cells. Testis-specific transcripts exhibited the opposite pattern, suggesting to Larsson et al. (1997) that in both humans and mice, these testis-specific mtTFA transcripts downregulate mtTFA protein levels in mammalian mitochondria. Their findings demonstrated that mtTFA does not have a critical role in nucleus, suggested a mechanism for reducing mtDNA copy number during spermatogenesis, and had implications for the understanding of strictly maternal transmission of mtDNA. </p><p>Mitochondrial nucleoids are large complexes containing, on average, 5 to 7 mtDNA genomes and several proteins involved in mtDNA replication and transcription, as well as related processes. Bogenhagen et al. (2008) had previously shown that TFAM was associated with native purified HeLa cell nucleoids. Using a formaldehyde crosslinking technique, they found that TFAM copurified with mtDNA and was a core nucleoid protein. Bogenhagen et al. (2008) confirmed these findings by Western blot analysis. </p><p>Yamamoto et al. (2012) observed upregulated expression of Foxj3 (616035) and mtTFA in differentiated mouse C2C12 myotubes, concomitant with downregulation of the regulatory microRNA Mir494 (616036). Knockdown and overexpression studies with Western blot, microarray, and reporter gene analyses showed that Mir494 downregulated translation of Foxj3 and mtTFA mRNAs in proliferating C2C12 myoblasts by binding to conserved target sequences in their 3-prime UTRs. Mir494 did not cause mRNA degradation. Endurance exercise in mice stimulated mitochondrial biogenesis in skeletal muscle, concomitant with decreased expression of Mir494 and elevated expression of Foxj3 and mtTFA. Yamamoto et al. (2012) concluded that FOXJ3 and mtTFA promote mitochondrial biogenesis and that MIR494 inhibits their expression and activity. </p><p>West et al. (2015) showed that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signaling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, the authors found that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (613973) and promotes STING (612374)/IRF3 (603734)-dependent signaling to elevate interferon-stimulated gene expression, potentiate type I interferon responses, and confer broad viral resistance. Furthermore, West et al. (2015) demonstrated that herpes viruses induce mtDNA stress, which enhances antiviral signaling and type I interferon responses during infection. West et al. (2015) concluded that their results further demonstrated that mitochondria are central participants in innate immunity, identified mtDNA stress as a cell-intrinsic trigger of antiviral signaling, and suggested that cellular monitoring of mtDNA homeostasis cooperates with canonical virus-sensing mechanisms to fully engage antiviral innate immunity. </p>
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</span>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</div>
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<span class="mim-text-font">
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<p>By Southern blot analysis of restriction enzyme digests of human/Chinese hamster somatic cell hybrid lines, Milatovich et al. (1992) mapped TFAM sequences, which they called MTTF1, to 3 different chromosomes: chromosomes 10, 7p, and 11q.</p><p>By PCR-based screening of a somatic cell hybrid panel and by fluorescence in situ hybridization, Tiranti et al. (1995) assigned the TFAM gene to 10q21. </p><p>Scott (2007) stated that the sequences mapped to chromosomes 7p (TCF6L1) and 11q (MTTF1, or TCF6L3) are pseudogenes.</p><p>Larsson et al. (1997) mapped the mouse mitochondrial transcription factor A gene (Tfam) to the central part of mouse chromosome 10. This region exhibits syntenic homology with human 10q21. </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p>In 2 sibs, born of consanguineous parents of Colombian-Basque descent, with mitochondrial DNA depletion syndrome-15 (MTDPS15; 617156), Stiles et al. (2016) identified a homozygous missense mutation in the TFAM gene (P178L; 600438.0001). The mutation, which was found by exome sequencing, segregated with the disorder in the family. Patient fibroblasts showed increased TFAM mRNA but decreased protein levels, consistent with a compensatory mechanism. Patient fibroblasts also had decreased mtDNA copy number, decreased basal respiration, decreased number of nucleoids, and presence of abnormal nucleoid aggregates compared to controls, all indicative of mitochondrial dysfunction. The patients had neonatal onset of rapidly progressive liver failure, resulting in death in infancy. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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<p>The regulation of mitochondrial DNA expression is crucial for mitochondrial biogenesis during development and differentiation. Larsson et al. (1998) disrupted the mouse Tfam gene by gene targeting. Heterozygous mice exhibited reduced mtDNA copy number and respiratory chain deficiency in heart. Homozygous knockout embryos exhibited a severe mtDNA depletion with abolished oxidative phosphorylation. Mutant embryos proceed through implantation and gastrulation, but die before embryonic day (E)10.5. Thus, Tfam is the first mammalian protein demonstrated to regulate mtDNA copy number in vivo and is essential for mitochondrial biogenesis and embryonic development. </p><p>Wang et al. (1999) reported that hallmarks of mtDNA mutation disorders can be reproduced in the mouse using a conditional mutation strategy to manipulate the expression of the gene encoding mitochondrial transcription factor A (Tfam), which regulates transcription and replication of mtDNA. Using a loxP-flanked Tfam allele in combination with a cre-recombinase transgene under control of the muscle creatine kinase promoter, they disrupted Tfam in heart and muscle. Mutant animals developed a mosaic cardiac-specific progressive respiratory chain deficiency, dilated cardiomyopathy, and atrioventricular heart conduction blocks, and died at 2 to 4 weeks of age. This animal model reproduced biochemical, morphologic, and physiologic features of the dilated cardiomyopathy of Kearns-Sayre syndrome (530000). The findings provided genetic evidence that the respiratory chain is critical for normal heart function. The method should make it possible to disrupt oxidative phosphorylation in virtually any organ of the mouse by expressing cre-recombinase in a tissue-specific manner. This system might shed light on the role of oxidative phosphorylation in aging and in the pathogenesis of common human disorders such as heart failure, diabetes mellitus, and neurodegenerative diseases. </p><p>Li et al. (2000) described a heart-knockout strain obtained by mating Tfam(loxP) mice to animals expressing cre-recombinase from the alpha-myosin heavy chain (Myhca; 160710) promoter. This promoter is active from embryonic day 8, and the knockouts had onset of mitochondrial cardiomyopathy during embryogenesis. The age of onset of cardiac respiratory chain dysfunction could thus be controlled by temporal regulation of cre-recombinase expression. Approximately 75% of the knockouts died in the neonatal period, whereas, surprisingly, approximately 25% survived for several months before dying from dilated cardiomyopathy with atrioventricular heart conduction blocks. Modifying genes affect the life span of knockouts, because approximately 95% of the knockout offspring from an intercross of the longer-living knockouts survived the neonatal period. Thus, the tissue-specific knockouts described by Li et al. (2000) not only reproduced important pathophysiologic features of mitochondrial cardiomyopathy but also provided a powerful system by which to identify modifying genes of potential therapeutic value. </p><p>Ekstrand et al. (2004) generated PAC transgenic mice ubiquitously expressing human TFAM. Expression of the human TFAM protein in the mouse did not result in downregulation of endogenous Tfam expression, thus resulting in a general increase of mtDNA copy number. Using a combination of mice with TFAM overexpression and TFAM knockout, the authors demonstrated that mtDNA copy number is directly proportional to the total TFAM protein levels. The expression of human TFAM in the mouse resulted in upregulation of mtDNA copy number without increasing respiratory chain capacity or mitochondrial mass. The authors proposed a novel role for TFAM in direct regulation of mtDNA copy number in mammals. </p><p>Aydin et al. (2009) used mice with skeletal muscle-specific disruption of Tfam to study whether change in cellular Ca2+ handling is part of the mechanism of muscle dysfunction in mitochondrial myopathy. Muscles of Tfam knockout mice show a progressive deterioration in respiratory chain function over their approximately 4-month life span. Force measurements were combined with measurements of cytosolic Ca2+, mitochondrial Ca2+, and membrane potential and reactive oxygen species in intact adult muscle fibers. There was reduced sarcoplasmic reticulum Ca2+ storage capacity in Tfam knockout muscles due to a decreased expression of calsequestrin-1 (CASQ1; 114250). There were no signs of oxidative stress in Tfam knockout cells, whereas they displayed increased mitochondrial Ca2+ levels during repeated contractions. Mitochondrial Ca2+ levels remained elevated long after the end of stimulation in muscle cells from Tfam knockout mice, and the increase was smaller in the presence of the cyclophilin D (601753)-binding inhibitor cyclosporin A. The mitochondrial membrane potential in Tfam knockout cells did not decrease during repeated contractions. The authors suggested that the observed changes in Ca2+ handling may be adaptive responses with long-term detrimental effects. Reduced sarcoplasmic reticulum Ca2+ release may decrease ATP expenditure, but it also induces muscle weakness. Increased Ca2+ levels in the mitochondrial matrix may stimulate mitochondrial metabolism acutely, but may also trigger cell damage. </p><p>Desdin-Mico et al. (2020) found that mice with T cell-specific deletion of Tfam had T cells with dysfunctional mitochondria that acted as accelerators of senescence. These cells instigated multiple aging-related features in mutant mice, including metabolic, cognitive, physical, and cardiovascular alterations, that resulted in premature death. T-cell metabolic failure induced accumulation of circulating cytokines, resembling chronic inflammation characteristic of aging, and this cytokine storm acted as a systemic inducer of senescence. Blocking Tnf (191160) signaling or preventing senescence with nicotinamide adenine dinucleotide precursors partially rescued premature aging in mutant mice. Desdin-Mico et al. (2020) concluded that T cells can regulate organismal fitness and life span, highlighting the importance of tight immunometabolic control in both aging and the onset of age-associated diseases. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>1 Selected Example):</strong>
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<span class="mim-font">
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<strong>.0001 MITOCHONDRIAL DNA DEPLETION SYNDROME 15 (HEPATOCEREBRAL TYPE) (1 family)</strong>
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TFAM, PRO178LEU
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SNP: rs757075712,
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gnomAD: rs757075712,
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ClinVar: RCV000256433
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<p>In 2 sibs, born of consanguineous parents of Colombian-Basque descent, with mitochondrial DNA depletion syndrome-15 (MTDPS15; 617156), Stiles et al. (2016) identified a homozygous c.533C-T transition (c.533C-T, NM_003201.2) in the TFAM gene, resulting in a pro178-to-leu (P178L) substitution in the HMG box B domain, which is involved in mtDNA binding and compaction. The mutation was predicted to result in steric hindrance and decreased binding ability of TFAM to mtDNA. The mutation, which was found by exome sequencing, segregated with the disorder in the family, and was found in 2 of 118,504 chromosomes in the ExAC database. Patient fibroblasts showed increased TFAM mRNA but decreased protein levels, consistent with a compensatory mechanism. Patient cells also had decreased mtDNA copy number, decreased basal respiration, decreased number of nucleoids, and presence of abnormal nucleoid aggregates compared to controls. The patients had neonatal onset of rapidly progressive liver failure, resulting in death in infancy. </p>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Tominaga et al. (1992)
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<span class="mim-font">
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<strong>REFERENCES</strong>
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<strong>T cells with dysfunctional mitochondria induce multimorbidity and premature senescence.</strong>
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Larsson, N.-G., Wang, J., Wilhelmsson, H., Oldfors, A., Rustin, P., Lewandoski, M., Barsh, G. S., Clayton, D. A.
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Milatovich, A., Parisi, M. A., Poulton, J., Clayton, D. A., Francke, U.
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<strong>Sequences homologous to MTTF1, mitochondrial transcription factor 1, are located on human chromosomes 7 (7pter-cen), 10 and 11 (11cen-qter). (Abstract)</strong>
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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Ada Hamosh - updated : 10/20/2020<br>Cassandra L. Kniffin - updated : 10/13/2016<br>Ada Hamosh - updated : 06/26/2015<br>Patricia A. Hartz - updated : 9/26/2014<br>George E. Tiller - updated : 4/17/2009<br>Patricia A. Hartz - updated : 9/24/2008<br>George E. Tiller - updated : 9/18/2006<br>Victor A. McKusick - updated : 4/20/2000<br>Victor A. McKusick - updated : 12/29/1998<br>Victor A. McKusick - updated : 2/27/1998<br>Victor A. McKusick - updated : 4/15/1997<br>Victor A. McKusick - updated : 4/4/1997
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Creation Date:
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Victor A. McKusick : 3/6/1995
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mgross : 10/20/2020<br>carol : 06/04/2019<br>alopez : 10/17/2016<br>ckniffin : 10/13/2016<br>alopez : 06/26/2015<br>carol : 10/1/2014<br>mgross : 9/30/2014<br>mcolton : 9/26/2014<br>alopez : 4/17/2009<br>mgross : 9/25/2008<br>terry : 9/24/2008<br>carol : 9/20/2007<br>alopez : 9/18/2006<br>carol : 8/1/2005<br>terry : 4/20/2000<br>carol : 12/29/1998<br>alopez : 12/21/1998<br>alopez : 2/27/1998<br>terry : 2/27/1998<br>jenny : 4/15/1997<br>terry : 4/4/1997<br>jenny : 4/4/1997<br>terry : 4/2/1997<br>jamie : 2/5/1997<br>carol : 3/7/1995<br>carol : 3/6/1995
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