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Entry
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- *600857 - SUCCINATE DEHYDROGENASE COMPLEX, FLAVOPROTEIN SUBUNIT A; SDHA
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*600857</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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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 role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#history">History</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/600857">Table View</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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</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=ENSG00000073578;t=ENST00000264932" 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=6389" 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=600857" 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=ENSG00000073578;t=ENST00000264932" 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_001294332,NM_001330758,NM_004168,XM_011514072,XM_011514073,XM_047417467,XR_007058614" 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_004168" 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=600857" 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=02914&isoform_id=02914_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/SDHA" 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/347134,506338,1169337,1176426,5759173,12655061,26996830,62087562,89574179,119571367,119571368,119571369,156416003,158256058,193785980,193787743,194380060,194381536,661567360,767934511,767934514,1061899942,2217356599,2462603461,2462603463,2462603465" 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/P31040" 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=6389" 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=ENSG00000073578;t=ENST00000264932" 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=SDHA" 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=SDHA" 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+6389" 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/SDHA" 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:6389" 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/6389" 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=chr5&hgg_gene=ENST00000651543.1&hgg_start=218320&hgg_end=268746&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://search.clinicalgenome.org/kb/genes/HGNC:10680" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/sdha" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=600857[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=600857[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/SDHA/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000073578" 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=SDHA" 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=SDHA" 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=SDHA" 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="http://www.LOVD.nl/SDHA" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=SDHA&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/PA35605" 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:10680" 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/FBgn0261439.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:1914195" 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/SDHA#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:1914195" 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/6389/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=6389" 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="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00015391;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00015391 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00016392;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00016392 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-040426-874" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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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:6389" 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=SDHA&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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600857
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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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SUCCINATE DEHYDROGENASE COMPLEX, FLAVOPROTEIN SUBUNIT A; SDHA
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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>
|
|
<span class="mim-font">
|
|
SUCCINATE DEHYDROGENASE COMPLEX, SUBUNIT A, FLAVOPROTEIN<br />
|
|
SUCCINATE DEHYDROGENASE 1, S. CEREVISIAE, HOMOLOG OF<br />
|
|
SDH1, HOMOLOG OF
|
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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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<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">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=SDHA" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SDHA</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">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/5/9?start=-3&limit=10&highlight=9">5p15.33</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr5:218320-268746&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'})">5:218,320-268,746</a> </span>
|
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</em>
|
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</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>
|
|
<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">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=613642,252011,619259,614165" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/5/9?start=-3&limit=10&highlight=9">
|
|
5p15.33
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
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|
|
<td>
|
|
<span class="mim-font">
|
|
Cardiomyopathy, dilated, 1GG
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/613642"> 613642 </a>
|
|
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
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|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
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|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<p>Complex II of the mitochondrial respiratory chain, also known as succinate dehydrogenase or succinate:ubiquinone oxidoreductase (<a href="https://enzyme.expasy.org/EC/1.3.5.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 1.3.5.1</a>), consists of 4 nuclear-encoded polypeptides. In order of decreasing molecular mass, these are the flavoprotein subunit (SDHA), the iron sulfur protein subunit (SDHB; <a href="/entry/185470">185470</a>), and the integral membrane protein subunits SDHC (<a href="/entry/602413">602413</a>) and SDHD (<a href="/entry/602690">602690</a>) (summary by <a href="#10" class="mim-tip-reference" title="Hirawake, H., Wang, H., Kuramochi, T., Kojima, S., Kita, K. <strong>Human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of the flavoprotein (Fp) subunit of liver mitochondria.</strong> J. Biochem. 116: 221-227, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7798181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7798181</a>] [<a href="https://doi.org/10.1093/oxfordjournals.jbchem.a124497" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7798181">Hirawake et al., 1994</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7798181" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#10" class="mim-tip-reference" title="Hirawake, H., Wang, H., Kuramochi, T., Kojima, S., Kita, K. <strong>Human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of the flavoprotein (Fp) subunit of liver mitochondria.</strong> J. Biochem. 116: 221-227, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7798181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7798181</a>] [<a href="https://doi.org/10.1093/oxfordjournals.jbchem.a124497" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7798181">Hirawake et al. (1994)</a> isolated a cDNA corresponding to the flavoprotein subunit of SDH from a human liver cDNA library. The deduced 621-amino acid protein has a molecular mass of approximately 68 kD and shows high homology to the bovine heart flavoprotein subunit. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7798181" 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="#14" class="mim-tip-reference" title="Morris, A. A. M., Farnsworth, L., Ackrell, B. A. C., Turnbull, D. M., Birch-Machin, M. A. <strong>The cDNA sequence of the flavoprotein subunit of human heart succinate dehydrogenase.</strong> Biochim. Biophys. Acta 1185: 125-128, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8142412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8142412</a>] [<a href="https://doi.org/10.1016/0005-2728(94)90203-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8142412">Morris et al. (1994)</a> cloned and sequenced the flavoprotein subunit of human heart SDH. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8142412" 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="#5" class="mim-tip-reference" title="Burnichon, N,, Briere, J.-J., Libe, R., Vescovo, L., Riviere, J., Tissier, F., Jouanno, E., Jeunemaitre, X., Benit, P., Tzagoloff, A., Rustin, P., Bertherat, J., Favier, J., Gimenez-Roqueplo, A.-P. <strong>SDHA is a tumor suppressor gene causing paraganglioma.</strong> Hum. Molec. Genet. 19: 3011-3020, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20484225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20484225</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20484225[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddq206" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20484225">Burnichon et al. (2010)</a> determined that the SDHA gene is highly polymorphic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20484225" 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="#13" class="mim-tip-reference" title="Mills, E. L., Pierce, K. A., Jedrychowski, M. P., Garrity, R., Winther, S., Vidoni, S., Yoneshiro, T., Spinelli, J. B., Lu, G. Z., Kazak, L., Banks, A. S., Haigis, M. C., Kajimura, S., Murphy, M. P., Gygi, S. P., Clish, C. B, Chouchani, E. T. <strong>Accumulation of succinate controls activation of adipose tissue thermogenesis.</strong> Nature 560: 102-106, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30022159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30022159</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30022159[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/s41586-018-0353-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30022159">Mills et al. (2018)</a> showed that substantial and selective accumulation of the tricarboxylic acid cycle intermediate succinate is a metabolic signature of adipose tissue thermogenesis upon activation by exposure to cold. Succinate accumulation occurs independently of adrenergic signaling, and is sufficient to elevate thermogenic respiration in brown adipocytes. Selective accumulation of succinate may be driven by a capacity of brown adipocytes to sequester elevated circulating succinate. Furthermore, brown adipose tissue thermogenesis can be initiated by systemic administration of succinate in mice. Succinate from the extracellular milieu is rapidly metabolized by brown adipocytes, and its oxidation by succinate dehydrogenase is required for activation of thermogenesis. <a href="#13" class="mim-tip-reference" title="Mills, E. L., Pierce, K. A., Jedrychowski, M. P., Garrity, R., Winther, S., Vidoni, S., Yoneshiro, T., Spinelli, J. B., Lu, G. Z., Kazak, L., Banks, A. S., Haigis, M. C., Kajimura, S., Murphy, M. P., Gygi, S. P., Clish, C. B, Chouchani, E. T. <strong>Accumulation of succinate controls activation of adipose tissue thermogenesis.</strong> Nature 560: 102-106, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30022159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30022159</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30022159[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/s41586-018-0353-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30022159">Mills et al. (2018)</a> identified a mechanism whereby succinate dehydrogenase-mediated oxidation of succinate initiates production of reactive oxygen species, and drives thermogenic respiration, whereas inhibition of succinate dehydrogenase suppresses thermogenesis. Finally, <a href="#13" class="mim-tip-reference" title="Mills, E. L., Pierce, K. A., Jedrychowski, M. P., Garrity, R., Winther, S., Vidoni, S., Yoneshiro, T., Spinelli, J. B., Lu, G. Z., Kazak, L., Banks, A. S., Haigis, M. C., Kajimura, S., Murphy, M. P., Gygi, S. P., Clish, C. B, Chouchani, E. T. <strong>Accumulation of succinate controls activation of adipose tissue thermogenesis.</strong> Nature 560: 102-106, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30022159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30022159</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30022159[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/s41586-018-0353-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30022159">Mills et al. (2018)</a> showed that pharmacologic elevation of circulating succinate drives UCP1 (<a href="/entry/113730">113730</a>)-dependent thermogenesis by brown adipose tissue in vivo, which stimulates robust protection against diet-induced obesity and improves glucose tolerance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30022159" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In mammalian cells, <a href="#17" class="mim-tip-reference" title="Spinelli, J. B., Rosen, P. C., Sprenger, H.-G., Puszynska, A. M., Mann, J. L., Roessler, J. M., Cangelosi, A. L., Henne, A., Condon, K. J., Zhang, T., Kunchok, T., Lewis, C. A., Chandel, N. S., Sabatini, D. M. <strong>Fumarate is a terminal electron acceptor in the mammalian electron transport chain.</strong> Science 374: 1227-1237, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34855504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34855504</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34855504[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.abi7495" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34855504">Spinelli et al. (2021)</a> found that when oxygen reduction is impeded, mitochondrial complex I and dihydroorotate dehydrogenase (DHODH; <a href="/entry/126064">126064</a>) can still deposit electrons into the electron transport chain because the accumulation of ubiquinol drives the succinate dehydrogenase complex in reverse to enable electron deposition onto fumarate. Fumarate sustains DHODH and complex I activities by acting as the terminal electron acceptor, maintaining mitochondrial function under oxygen limitation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34855504" 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 fluorescence in situ hybridization, <a href="#4" class="mim-tip-reference" title="Bourgeron, T., Rustin, P., Chretien, D., Birch-Machin, M., Bourgeois, M., Viegas-Pequignot, E., Munnich, A., Rotig, A. <strong>Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency.</strong> Nature Genet. 11: 144-149, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550341</a>] [<a href="https://doi.org/10.1038/ng1095-144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550341">Bourgeron et al. (1995)</a> demonstrated that the flavoprotein subunit gene is duplicated in the human genome, present on chromosomes 3q29 and 5p15, with only the gene on chromosome 5 expressed in human/hamster somatic cell hybrids. The gene on chromosome 3q29 is a pseudogene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7550341" 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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In 2 sibs with mitochondrial complex II deficiency nuclear type 1 (MC2DN1; <a href="/entry/252011">252011</a>) presenting as Leigh syndrome (see <a href="/entry/256000">256000</a>), <a href="#4" class="mim-tip-reference" title="Bourgeron, T., Rustin, P., Chretien, D., Birch-Machin, M., Bourgeois, M., Viegas-Pequignot, E., Munnich, A., Rotig, A. <strong>Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency.</strong> Nature Genet. 11: 144-149, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550341</a>] [<a href="https://doi.org/10.1038/ng1095-144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550341">Bourgeron et al. (1995)</a> identified a homozygous mutation in the SHDA gene (R554W; <a href="#0001">600857.0001</a>). <a href="#4" class="mim-tip-reference" title="Bourgeron, T., Rustin, P., Chretien, D., Birch-Machin, M., Bourgeois, M., Viegas-Pequignot, E., Munnich, A., Rotig, A. <strong>Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency.</strong> Nature Genet. 11: 144-149, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550341</a>] [<a href="https://doi.org/10.1038/ng1095-144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550341">Bourgeron et al. (1995)</a> claimed that this was the first report of a nuclear gene mutation causing a mitochondrial respiratory chain deficiency in humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7550341" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with MC2DN1 manifesting as Leigh syndrome, <a href="#16" class="mim-tip-reference" title="Parfait, B., Chretien, D., Rotig, A., Marsac, C., Munnich, A., Rustin, P. <strong>Compound heterozygous mutations in the flavoprotein gene of the respiratory chain complex II in a patient with Leigh syndrome.</strong> Hum. Genet. 106: 236-243, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10746566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10746566</a>] [<a href="https://doi.org/10.1007/s004390051033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10746566">Parfait et al. (2000)</a> identified compound heterozygous 2 mutations in the SDHA gene (A524V, <a href="#0002">600857.0002</a>; M1L, <a href="#0003">600857.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10746566" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a female infant who died at 5.5 months of age following a respiratory infection and was found to have MC2DN1, <a href="#20" class="mim-tip-reference" title="Van Coster, R., Seneca, S., Smet, J., Van Hecke, R., Gerlo, E., Devreese, B., Van Beeumen, J., Leroy, J. G., De Meirleir, L., Lissens, W. <strong>Homozygous gly555-to-glu mutation in the nuclear-encoded 70 kDa flavoprotein gene causes instability of the respiratory chain complex II.</strong> Am. J. Med. Genet. 120A: 13-18, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12794685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12794685</a>] [<a href="https://doi.org/10.1002/ajmg.a.10202" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12794685">Van Coster et al. (2003)</a> identified homozygosity for a missense mutation in the SDHA gene (G555E; <a href="#0004">600857.0004</a>). The authors noted that the patient died in infancy before signs of Leigh syndrome could develop. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12794685" 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="Pagnamenta, A. T., Hargreaves, I. P., Duncan, A. J., Taanman, J.-W., Heales, S. J., Land, J. M., Bitner-Glindzicz, M., Leonard, J. V., Rahman, S. <strong>Phenotypic variability of mitochondrial disease caused by a nuclear mutation in complex II.</strong> Molec. Genet. Metab. 89: 214-221, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16798039/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16798039</a>] [<a href="https://doi.org/10.1016/j.ymgme.2006.05.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16798039">Pagnamenta et al. (2006)</a> reported a 10-year-old Palestinian boy with MC2DN1 manifest as Leigh syndrome in whom they identified homozygosity for the G555E mutation in the SDHA gene. <a href="#15" class="mim-tip-reference" title="Pagnamenta, A. T., Hargreaves, I. P., Duncan, A. J., Taanman, J.-W., Heales, S. J., Land, J. M., Bitner-Glindzicz, M., Leonard, J. V., Rahman, S. <strong>Phenotypic variability of mitochondrial disease caused by a nuclear mutation in complex II.</strong> Molec. Genet. Metab. 89: 214-221, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16798039/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16798039</a>] [<a href="https://doi.org/10.1016/j.ymgme.2006.05.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16798039">Pagnamenta et al. (2006)</a> noted that the patient previously reported by <a href="#20" class="mim-tip-reference" title="Van Coster, R., Seneca, S., Smet, J., Van Hecke, R., Gerlo, E., Devreese, B., Van Beeumen, J., Leroy, J. G., De Meirleir, L., Lissens, W. <strong>Homozygous gly555-to-glu mutation in the nuclear-encoded 70 kDa flavoprotein gene causes instability of the respiratory chain complex II.</strong> Am. J. Med. Genet. 120A: 13-18, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12794685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12794685</a>] [<a href="https://doi.org/10.1002/ajmg.a.10202" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12794685">Van Coster et al. (2003)</a> with the G555E mutation was also of Middle Eastern origin, suggesting the possibility of an ancestral mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16798039+12794685" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Dilated Cardiomyopathy 1GG</em></strong></p><p>
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In 15 Bedouin patients from a single tribe with neonatal dilated cardiomyopathy (CMD1GG; <a href="/entry/613642">613642</a>), <a href="#12" class="mim-tip-reference" title="Levitas, A., Muhammad, E., Harel, G., Saada, A., Caspi, V. C., Manor, E., Beck, J. C., Sheffield, V., Parvari, R. <strong>Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase.</strong> Europ. J. Hum. Genet. 18: 1160-1165, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20551992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20551992</a>] [<a href="https://doi.org/10.1038/ejhg.2010.83" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20551992">Levitas et al. (2010)</a> identified homozygosity for the G555E mutation in the SDHA gene. The patients all had a normal neuromuscular examination at presentation and follow-up, and psychomotor development was appropriate for age. Brain MRI was performed in 2 patients and showed no focal lesions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20551992" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Pheochromocytoma/Paraganglioma Syndrome 5</em></strong></p><p>
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In a woman with a catecholamine-secreting extraadrenal paraganglioma (PPGL5; <a href="/entry/614165">614165</a>), <a href="#5" class="mim-tip-reference" title="Burnichon, N,, Briere, J.-J., Libe, R., Vescovo, L., Riviere, J., Tissier, F., Jouanno, E., Jeunemaitre, X., Benit, P., Tzagoloff, A., Rustin, P., Bertherat, J., Favier, J., Gimenez-Roqueplo, A.-P. <strong>SDHA is a tumor suppressor gene causing paraganglioma.</strong> Hum. Molec. Genet. 19: 3011-3020, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20484225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20484225</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20484225[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddq206" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20484225">Burnichon et al. (2010)</a> identified a heterozygous germline mutation in the SDHA gene (R589W; <a href="#0005">600857.0005</a>). Tumor tissue showed loss of heterozygosity (LOH) at the SDHA locus. In vitro functional expression studies in the yeast homolog showed that the mutation resulted in a loss of SDH activity and rendered the mutant SDHA protein more susceptible to proteolysis. Studies of tumor tissue from the patient showed lack of SDHA and SDHB (<a href="/entry/185470">185470</a>) expression. Transcriptome analysis of the patient's tumor showed a similar pattern as that of other SDH-subunit mutated paraganglioma tumors, including stabilization of HIF1A (<a href="/entry/603348">603348</a>), consistent with activation of a pseudohypoxic pathway and angiogenesis. The findings indicated that SDHA, like other SDH subunits, can act as a tumor suppressor gene. Analysis of a large series of paragangliomas and pheochromocytomas found LOH at the SDHA locus in only 9 (4.5%) of 202 tumors, suggesting that it is an infrequent event. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20484225" 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="Korpershoek, E., Favier, J., Gaal, J., Burnichon, N., van Gessel, B., Oudijk, L., Badoual, C., Gadessaud, N., Venisse, A., Bayley, J.-P., van Dooren, M. F., de Herder, W. W., Tissier, F., Plouin, P.-F., van Nederveen, F. H., Dinjens, W. N. M., Gimenez-Roqueplo, A.-P., de Krijger, R. R. <strong>SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas.</strong> J. Clin. Endocr. Metab. 96: E1472-E1476, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21752896/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21752896</a>] [<a href="https://doi.org/10.1210/jc.2011-1043" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21752896">Korpershoek et al. (2011)</a> found that 7 of 316 pheochromocytomas and paragangliomas, including the SDHA-mutated paraganglioma described by <a href="#5" class="mim-tip-reference" title="Burnichon, N,, Briere, J.-J., Libe, R., Vescovo, L., Riviere, J., Tissier, F., Jouanno, E., Jeunemaitre, X., Benit, P., Tzagoloff, A., Rustin, P., Bertherat, J., Favier, J., Gimenez-Roqueplo, A.-P. <strong>SDHA is a tumor suppressor gene causing paraganglioma.</strong> Hum. Molec. Genet. 19: 3011-3020, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20484225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20484225</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20484225[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddq206" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20484225">Burnichon et al. (2010)</a>, were negative for SDHA immunostaining. All patients were found to carry a heterozygous mutation in the SDHA gene (<a href="#0005">600857.0005</a>; <a href="#0008">600857.0008</a>-<a href="#0009">600857.0009</a>), and all tumor tissue showed LOH for the wildtype SDHA allele. None of the patients had a family history of the disorder. All tumors were also negative for SDHB immunostaining, suggesting that impaired complex II formation results in SDHB degradation. The findings established SDHA as a tumor-suppressor gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21752896+20484225" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Neurodegeneration with Ataxia and Late-Onset Optic Atrophy</em></strong></p><p>
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In 2 adult sisters with neurodegeneration with ataxia and late-onset optic atrophy (NDAXOA; <a href="/entry/619259">619259</a>), who were originally reported by <a href="#19" class="mim-tip-reference" title="Taylor, R. W., Birch-Machin, M. A., Schaefer, J., Taylor, L., Shakir, R., Ackrell, B. A. C., Cochran, B., Bindoff, L. A., Jackson, M. J., Griffiths, P., Turnbull, D. M. <strong>Deficiency of complex II of the mitochondrial respiratory chain in late-onset optic atrophy and ataxia.</strong> Ann. Neurol. 39: 224-232, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8967754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8967754</a>] [<a href="https://doi.org/10.1002/ana.410390212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8967754">Taylor et al. (1996)</a>, <a href="#2" class="mim-tip-reference" title="Birch-Machin, M. A., Taylor, R. W., Cochran, B., Ackrell, B. A. C., Turnbull, D. M. <strong>Late-onset optic atrophy, ataxia, and myopathy associated with a mutation of a complex II gene.</strong> Ann. Neurol. 48: 330-335, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10976639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10976639</a>]" pmid="10976639">Birch-Machin et al. (2000)</a> identified a heterozygous missense mutation in the SDHA gene (R451C; <a href="#0011">600857.0011</a>). The mutation, which was found by direct sequencing, was not found in an unaffected sister or in 80 control samples. In vitro functional expression studies in E. coli showed almost no mitochondrial complex II or SDH activity compared to controls; there was decreased protein expression at the membrane. The evidence suggested that the mutation interfered with association of the FAD cofactor. Patient myoblasts showed normal membrane content of SDHA immunoreactive protein, but complex II and SDH activity were 50% of normal values. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8967754+10976639" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 affected members of a 2-generation family with NDAXOA, <a href="#6" class="mim-tip-reference" title="Courage, C., Jackson, C. B., Hahn, D., Euro, L., Nuoffer, J.-M., Gallati, S., Schaller, A. <strong>SDHA mutation with dominant transmission results in complex II deficiency with ocular, cardiac, and neurologic involvement.</strong> Am. J. Med. Genet. 173A: 225-230, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27683074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27683074</a>] [<a href="https://doi.org/10.1002/ajmg.a.37986" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27683074">Courage et al. (2017)</a> identified a heterozygous R451C mutation in the SDHA gene. Molecular modeling predicted that the mutation interfered with succinate binding, causing a loss of succinate dehydrogenase activity. Functional studies of the variant were not performed, but patient cells showed about a 50% decrease in complex II activity. The patients in this family also developed cardiomyopathy, including an infant who died at 7 months of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27683074" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), <a href="#7" class="mim-tip-reference" title="Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. <strong>High-throughput discovery of novel developmental phenotypes.</strong> Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27626380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27626380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27626380[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/nature19356" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27626380">Dickinson et al. (2016)</a> found that knockout of the mouse homolog of human SDHA is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27626380" 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>High similarity between yeast and human mitochondria allows functional genomic study of S. cerevisiae to be used in identifying human genes involved in disease (<a href="#9" class="mim-tip-reference" title="Foury, F. <strong>Human genetic diseases: a cross-talk between man and yeast.</strong> Gene 195: 1-10, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9300813/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9300813</a>] [<a href="https://doi.org/10.1016/s0378-1119(97)00140-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9300813">Foury, 1997</a>). A considerable number of heritable disorders had been attributed to defects in known nuclear-encoded mitochondrial proteins in humans. Many mitochondrial diseases remained unexplained, however, in part because only 40 to 60% of the presumed 700 to 1,000 proteins involved in mitochondrial function and biogenesis had been identified (<a href="#21" class="mim-tip-reference" title="Wallace, D. C. <strong>Mitochondrial diseases in man and mouse.</strong> Science 283: 1482-1488, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10066162/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10066162</a>] [<a href="https://doi.org/10.1126/science.283.5407.1482" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10066162">Wallace, 1999</a>). <a href="#18" class="mim-tip-reference" title="Steinmetz, L. M., Scharfe, C., Deutschbauer, A. M., Mokranjac, D., Herman, Z. S., Jones, T., Chu, A. M., Giaever, G., Prokisch, H., Oefner, P. J., Davis, R. W. <strong>Systematic screen for human disease genes in yeast.</strong> Nature Genet. 31: 400-404, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12134146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12134146</a>] [<a href="https://doi.org/10.1038/ng929" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12134146">Steinmetz et al. (2002)</a> applied a systematic functional screen using the preexisting whole-genome pool of yeast deletion mutants to identify mitochondrial proteins. A large number of measurements of strain fitness identified 466 genes whose deletions impaired mitochondrial respiration, 265 of which were new. The approach gave higher selection than other systematic approaches, including 5-fold greater selection than gene expression analysis. To apply these advantages to human disorders involving mitochondria, human orthologs were identified and linked to heritable diseases using genomic map positions. <a href="#18" class="mim-tip-reference" title="Steinmetz, L. M., Scharfe, C., Deutschbauer, A. M., Mokranjac, D., Herman, Z. S., Jones, T., Chu, A. M., Giaever, G., Prokisch, H., Oefner, P. J., Davis, R. W. <strong>Systematic screen for human disease genes in yeast.</strong> Nature Genet. 31: 400-404, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12134146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12134146</a>] [<a href="https://doi.org/10.1038/ng929" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12134146">Steinmetz et al. (2002)</a> identified 22 human mitochondria-related genes that give rise to disease and for which there was an associated quantitative deletion phenotype in yeast. They also identified new human candidate genes as the possible basis of mitochondria-related diseases, including spastic paraplegia-5A (<a href="/entry/270800">270800</a>), Friedreich ataxia-2 (FRDA2; <a href="/entry/601992">601992</a>), and 2 forms of optic atrophy: OPA2 (<a href="/entry/311050">311050</a>) and OPA4 (<a href="/entry/605293">605293</a>). Deletion in the yeast homolog suggested genes as the basis of the human disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9300813+10066162+12134146" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>11 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=600857[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs9809219 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs9809219;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs9809219?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs9809219" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs9809219" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009281 OR RCV000456631 OR RCV000573113 OR RCV000790927 OR RCV001818148 OR RCV003315222 OR RCV003473060 OR RCV005031432" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009281, RCV000456631, RCV000573113, RCV000790927, RCV001818148, RCV003315222, RCV003473060, RCV005031432" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009281...</a>
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<p>In 2 sibs with complex II mitochondrial respiratory chain deficiency nuclear type 1 (MC2DN1; <a href="/entry/252011">252011</a>) presenting as Leigh syndrome (see <a href="/entry/256000">256000</a>), <a href="#4" class="mim-tip-reference" title="Bourgeron, T., Rustin, P., Chretien, D., Birch-Machin, M., Bourgeois, M., Viegas-Pequignot, E., Munnich, A., Rotig, A. <strong>Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency.</strong> Nature Genet. 11: 144-149, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550341</a>] [<a href="https://doi.org/10.1038/ng1095-144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550341">Bourgeron et al. (1995)</a> demonstrated a 1684C-T transition in the succinate dehydrogenase flavoprotein subunit gene in a CpG dinucleotide, resulting in an arg554-to-trp (R554W) substitution in a conserved domain of the protein. Functional expression studies in an SDH-negative yeast strain transformed with the mutant R554W protein showed decreased catalytic activity (approximately 50% of controls). The mutation was absent from 120 controls. The sibs were originally described by <a href="#3" class="mim-tip-reference" title="Bourgeois, M., Goutieres, F., Chretien, D., Rustin, P., Munnich, A., Aicardi, J. <strong>Deficiency in complex II of the respiratory chain, presenting as a leukodystrophy in two sisters with Leigh syndrome.</strong> Brain Dev. 14: 404-408, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1492653/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1492653</a>] [<a href="https://doi.org/10.1016/s0387-7604(12)80349-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1492653">Bourgeois et al. (1992)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1492653+7550341" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852767 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852767;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137852767" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137852767" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009282 OR RCV000520939 OR RCV000649458 OR RCV002399314 OR RCV003473061" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009282, RCV000520939, RCV000649458, RCV002399314, RCV003473061" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009282...</a>
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<p>In a girl with mitochondrial complex II deficiency nuclear type 1 (MC2DN1; <a href="/entry/252011">252011</a>) presenting as Leigh syndrome (see <a href="/entry/256000">256000</a>), <a href="#16" class="mim-tip-reference" title="Parfait, B., Chretien, D., Rotig, A., Marsac, C., Munnich, A., Rustin, P. <strong>Compound heterozygous mutations in the flavoprotein gene of the respiratory chain complex II in a patient with Leigh syndrome.</strong> Hum. Genet. 106: 236-243, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10746566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10746566</a>] [<a href="https://doi.org/10.1007/s004390051033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10746566">Parfait et al. (2000)</a> identified compound heterozygous mutations in the SDHA gene: a C-to-T transition, resulting in an ala524-to-val (A524V) substitution, and an A-to-C transversion, resulting in a met1-to-leu (M1L; <a href="#0003">600857.0003</a>) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10746566" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1061517 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1061517;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs1061517?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1061517" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1061517" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009283 OR RCV001233940 OR RCV002415407 OR RCV003234897 OR RCV003450622" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009283, RCV001233940, RCV002415407, RCV003234897, RCV003450622" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009283...</a>
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<p>For discussion of the met1-to-leu (M1L) mutation in the SDHA gene that was found in compound heterozygous state in a patient with complex II deficiency nuclear type 1 (MC2DN1; <a href="/entry/252011">252011</a>) by <a href="#16" class="mim-tip-reference" title="Parfait, B., Chretien, D., Rotig, A., Marsac, C., Munnich, A., Rustin, P. <strong>Compound heterozygous mutations in the flavoprotein gene of the respiratory chain complex II in a patient with Leigh syndrome.</strong> Hum. Genet. 106: 236-243, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10746566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10746566</a>] [<a href="https://doi.org/10.1007/s004390051033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10746566">Parfait et al. (2000)</a>, see <a href="#0002">600857.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10746566" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137852768 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852768;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs137852768?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137852768" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137852768" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009284 OR RCV000009286 OR RCV001221088" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009284, RCV000009286, RCV001221088" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009284...</a>
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<p><strong><em>Mitochondrial Complex II Deficiency, Nuclear Type 1</em></strong></p><p>
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In a patient with mitochondrial complex II deficiency nuclear type 1 (MC2DN1; <a href="/entry/252011">252011</a>), born of first-cousin parents, <a href="#20" class="mim-tip-reference" title="Van Coster, R., Seneca, S., Smet, J., Van Hecke, R., Gerlo, E., Devreese, B., Van Beeumen, J., Leroy, J. G., De Meirleir, L., Lissens, W. <strong>Homozygous gly555-to-glu mutation in the nuclear-encoded 70 kDa flavoprotein gene causes instability of the respiratory chain complex II.</strong> Am. J. Med. Genet. 120A: 13-18, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12794685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12794685</a>] [<a href="https://doi.org/10.1002/ajmg.a.10202" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12794685">Van Coster et al. (2003)</a> identified a homozygous 1664G-A transition in exon 13 of the SDHA gene, resulting in a gly555-to-glu (G555E) substitution. The patient died at 5.5 months of age following a respiratory infection. Crossreacting material (CRM) for flavoprotein as well as iron-containing protein was decreased, and CRM for the entire complex II was reduced even more. The observation prompted speculation of a labile interaction between iron-containing protein and flavoprotein polypeptides and of a key role of the amino acid at position 555 in the interacting domain. The observation pointed to the fragile equilibrium of intermediate metabolism in infants with complex II deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12794685" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 10-year-old boy with relatively mild Leigh syndrome and isolated deficiency of mitochondrial complex II and relatively mild Leigh syndrome, who was born of consanguineous Palestinian parents, <a href="#15" class="mim-tip-reference" title="Pagnamenta, A. T., Hargreaves, I. P., Duncan, A. J., Taanman, J.-W., Heales, S. J., Land, J. M., Bitner-Glindzicz, M., Leonard, J. V., Rahman, S. <strong>Phenotypic variability of mitochondrial disease caused by a nuclear mutation in complex II.</strong> Molec. Genet. Metab. 89: 214-221, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16798039/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16798039</a>] [<a href="https://doi.org/10.1016/j.ymgme.2006.05.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16798039">Pagnamenta et al. (2006)</a> identified homozygosity for the G555E mutation in the SDHA gene. The unaffected parents were heterozygous for the mutation, which was not found in 60 controls. The authors noted that the patient previously reported by <a href="#20" class="mim-tip-reference" title="Van Coster, R., Seneca, S., Smet, J., Van Hecke, R., Gerlo, E., Devreese, B., Van Beeumen, J., Leroy, J. G., De Meirleir, L., Lissens, W. <strong>Homozygous gly555-to-glu mutation in the nuclear-encoded 70 kDa flavoprotein gene causes instability of the respiratory chain complex II.</strong> Am. J. Med. Genet. 120A: 13-18, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12794685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12794685</a>] [<a href="https://doi.org/10.1002/ajmg.a.10202" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12794685">Van Coster et al. (2003)</a> with the G555E mutation was also of Middle Eastern origin, suggesting the possibility of an ancestral mutation. <a href="#15" class="mim-tip-reference" title="Pagnamenta, A. T., Hargreaves, I. P., Duncan, A. J., Taanman, J.-W., Heales, S. J., Land, J. M., Bitner-Glindzicz, M., Leonard, J. V., Rahman, S. <strong>Phenotypic variability of mitochondrial disease caused by a nuclear mutation in complex II.</strong> Molec. Genet. Metab. 89: 214-221, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16798039/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16798039</a>] [<a href="https://doi.org/10.1016/j.ymgme.2006.05.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16798039">Pagnamenta et al. (2006)</a> stated that both patients had comparable activities and stability of mitochondrial respiratory chain enzymes. Biochemical studies of cultured fibroblasts showed that the size of the band corresponding to the partially assembled complex II differed slightly between the 2 patients; however, their phenotypic variability remained unexplained. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16798039+12794685" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Dilated Cardiomyopathy 1GG</em></strong></p><p>
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In 15 Bedouin patients from a single tribe with neonatal dilated cardiomyopathy (CMD1GG; <a href="/entry/613642">613642</a>), including 13 patients from 2 consanguineous families and 2 sporadic patients, <a href="#12" class="mim-tip-reference" title="Levitas, A., Muhammad, E., Harel, G., Saada, A., Caspi, V. C., Manor, E., Beck, J. C., Sheffield, V., Parvari, R. <strong>Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase.</strong> Europ. J. Hum. Genet. 18: 1160-1165, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20551992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20551992</a>] [<a href="https://doi.org/10.1038/ejhg.2010.83" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20551992">Levitas et al. (2010)</a> identified homozygosity for the G555E mutation in the SDHA gene. The patients all had a normal neuromuscular examination at presentation and follow-up, and psychomotor development was appropriate for age. Brain MRI was performed in 2 patients and showed no focal lesions. <a href="#12" class="mim-tip-reference" title="Levitas, A., Muhammad, E., Harel, G., Saada, A., Caspi, V. C., Manor, E., Beck, J. C., Sheffield, V., Parvari, R. <strong>Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase.</strong> Europ. J. Hum. Genet. 18: 1160-1165, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20551992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20551992</a>] [<a href="https://doi.org/10.1038/ejhg.2010.83" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20551992">Levitas et al. (2010)</a> noted that the unaffected father of 1 of the patients was also homozygous for the G555E mutation, and he had 3 sibs who had died at a young age due to cardiovascular failure. Evaluation of other subunits of complex II (SDHB, <a href="/entry/185470">185470</a>; SDHD, <a href="/entry/602690">602690</a>) and a candidate modifier gene (SDHAF1; <a href="/entry/612848">612848</a>) showed no difference between the father, his affected son, and other Bedouin patients. The enzymatic activity of the father's complex II was decreased by 42% and was more similar to that of the other patients than to the heterozygous mother or controls. <a href="#12" class="mim-tip-reference" title="Levitas, A., Muhammad, E., Harel, G., Saada, A., Caspi, V. C., Manor, E., Beck, J. C., Sheffield, V., Parvari, R. <strong>Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase.</strong> Europ. J. Hum. Genet. 18: 1160-1165, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20551992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20551992</a>] [<a href="https://doi.org/10.1038/ejhg.2010.83" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20551992">Levitas et al. (2010)</a> stated that they did not have an explanation for the normal phenotype of the father. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20551992" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 5</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387906780 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906780;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs387906780?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906780" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906780" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000023042 OR RCV000554026 OR RCV000564186 OR RCV001799611 OR RCV003162258 OR RCV003473121" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023042, RCV000554026, RCV000564186, RCV001799611, RCV003162258, RCV003473121" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023042...</a>
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<p>In a woman with a catecholamine-secreting extraadrenal paraganglioma (PPGL5; <a href="/entry/614165">614165</a>), <a href="#5" class="mim-tip-reference" title="Burnichon, N,, Briere, J.-J., Libe, R., Vescovo, L., Riviere, J., Tissier, F., Jouanno, E., Jeunemaitre, X., Benit, P., Tzagoloff, A., Rustin, P., Bertherat, J., Favier, J., Gimenez-Roqueplo, A.-P. <strong>SDHA is a tumor suppressor gene causing paraganglioma.</strong> Hum. Molec. Genet. 19: 3011-3020, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20484225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20484225</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20484225[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddq206" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20484225">Burnichon et al. (2010)</a> identified a heterozygous germline 1765C-T transition in the SDHA gene, resulting in an arg589-to-trp (R589W) substitution at a highly conserved residue. The mutation was not found in 740 control chromosomes. Tumor tissue showed loss of heterozygosity (LOH) at the SDHA locus. In vitro functional expression studies in the yeast homolog showed that the mutation resulted in a loss of SDH activity and rendered the mutant SDHA protein more susceptible to proteolysis. Studies of tumor tissue from the patient showed lack of SDHA and SDHB (<a href="/entry/185470">185470</a>) expression. Transcriptome analysis of the patient's tumor showed a similar pattern as that of other SDH-subunit mutated paraganglioma tumors, including stabilization of HIF1A (<a href="/entry/603348">603348</a>), consistent with activation of a pseudohypoxic pathway and angiogenesis. The findings indicated that SDHA, like other SDH subunits, can act as a tumor suppressor gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20484225" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs151266052 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs151266052;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs151266052?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs151266052" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs151266052" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000032785 OR RCV000232220 OR RCV000563852 OR RCV001719715 OR RCV001818204" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032785, RCV000232220, RCV000563852, RCV001719715, RCV001818204" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032785...</a>
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<p>In a boy with mitochondrial complex II deficiency nuclear type 1 (MC2DN1; <a href="/entry/252011">252011</a>) manifest as cardiomyopathy and leukoencephalopathy, <a href="#1" class="mim-tip-reference" title="Alston, C. L., Davison, J. E., Meloni, F., van der Westhuizen, F. H., He, L., Hornig-Do, H.-T., Peet, A. C., Gissen, P., Goffrini, P., Ferrero, I., Wassmer, E., McFarland, R., Taylor, R. W. <strong>Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency.</strong> J. Med. Genet. 49: 569-577, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22972948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22972948</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22972948[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/10.1136/jmedgenet-2012-101146" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22972948">Alston et al. (2012)</a> identified compound heterozygosity for 2 mutations in the SDHA gene: a 1523C-T transition in exon 11 resulting in a thr508-to-ile (T508I) substitution, and a 1526C-T transition in exon 11 resulting in a ser509-to-leu (S509L; <a href="#0007">600857.0007</a>) substitution. Both mutations occurred at highly conserved residues within the catalytic flavoprotein subunit of the complex. Each unaffected parent was heterozygous for 1 of the mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22972948" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs397514541 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514541;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs397514541?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397514541" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397514541" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the ser509-to-leu (S509L) mutation in the SDHA gene that was found in compound heterozygous state in a patient with mitochondrial complex II deficiency nuclear type 1 (MC2DN1; <a href="/entry/252011">252011</a>) by <a href="#1" class="mim-tip-reference" title="Alston, C. L., Davison, J. E., Meloni, F., van der Westhuizen, F. H., He, L., Hornig-Do, H.-T., Peet, A. C., Gissen, P., Goffrini, P., Ferrero, I., Wassmer, E., McFarland, R., Taylor, R. W. <strong>Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency.</strong> J. Med. Genet. 49: 569-577, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22972948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22972948</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22972948[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/10.1136/jmedgenet-2012-101146" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22972948">Alston et al. (2012)</a>, see <a href="#0006">600857.0006</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22972948" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 5</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs142441643 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs142441643;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs142441643?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs142441643" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs142441643" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000131808 OR RCV000148026 OR RCV000170328 OR RCV000413945 OR RCV000627791 OR RCV000722034 OR RCV001089554 OR RCV001257553 OR RCV001762318 OR RCV001799624 OR RCV002478402 OR RCV003330507 OR RCV003335126 OR RCV003474779" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000131808, RCV000148026, RCV000170328, RCV000413945, RCV000627791, RCV000722034, RCV001089554, RCV001257553, RCV001762318, RCV001799624, RCV002478402, RCV003330507, RCV003335126, RCV003474779" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000131808...</a>
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<p>In 4 Dutch patients with paragangliomas (PPGL5; <a href="/entry/614165">614165</a>), <a href="#11" class="mim-tip-reference" title="Korpershoek, E., Favier, J., Gaal, J., Burnichon, N., van Gessel, B., Oudijk, L., Badoual, C., Gadessaud, N., Venisse, A., Bayley, J.-P., van Dooren, M. F., de Herder, W. W., Tissier, F., Plouin, P.-F., van Nederveen, F. H., Dinjens, W. N. M., Gimenez-Roqueplo, A.-P., de Krijger, R. R. <strong>SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas.</strong> J. Clin. Endocr. Metab. 96: E1472-E1476, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21752896/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21752896</a>] [<a href="https://doi.org/10.1210/jc.2011-1043" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21752896">Korpershoek et al. (2011)</a> identified a heterozygous germline c.91C-T transition (c.91C-T, NM_004168) in the SDHA gene, resulting in an arg31-to-ter (R31X) substitution. The mutation was found in 2 (0.3%) of 692 Dutch controls. All corresponding tumors showed loss of heterozygosity for SDHA and lack of SDHA and SDHB (<a href="/entry/185470">185470</a>) immunostaining. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21752896" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 5</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs200397144 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs200397144;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs200397144?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs200397144" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs200397144" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000148027 OR RCV000163558 OR RCV000464783 OR RCV000762143 OR RCV000765834 OR RCV001824123 OR RCV003474794" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000148027, RCV000163558, RCV000464783, RCV000762143, RCV000765834, RCV001824123, RCV003474794" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000148027...</a>
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<p>In a French patient with paragangliomas (PGL5; <a href="/entry/614165">614165</a>), <a href="#11" class="mim-tip-reference" title="Korpershoek, E., Favier, J., Gaal, J., Burnichon, N., van Gessel, B., Oudijk, L., Badoual, C., Gadessaud, N., Venisse, A., Bayley, J.-P., van Dooren, M. F., de Herder, W. W., Tissier, F., Plouin, P.-F., van Nederveen, F. H., Dinjens, W. N. M., Gimenez-Roqueplo, A.-P., de Krijger, R. R. <strong>SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas.</strong> J. Clin. Endocr. Metab. 96: E1472-E1476, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21752896/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21752896</a>] [<a href="https://doi.org/10.1210/jc.2011-1043" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21752896">Korpershoek et al. (2011)</a> identified a heterozygous germline c.1753C-T transition (c.1753C-T, NM_004168) in the SDHA gene, resulting in an arg585-to-trp (R585W) substitution. The mutation was found in 1 (0.1%) of 972 Dutch controls. Tumor tissue showed loss of heterozygosity for SDHA and lack of SDHA and SDHB (<a href="/entry/185470">185470</a>) immunostaining. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21752896" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 5</strong>
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SDHA, ARG75TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs781764920 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs781764920;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs781764920?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs781764920" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs781764920" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000191050 OR RCV000481058 OR RCV000575496 OR RCV000684793 OR RCV002492875 OR RCV003474945" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000191050, RCV000481058, RCV000575496, RCV000684793, RCV002492875, RCV003474945" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000191050...</a>
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<p>In a 20-year-old woman with paragangliomas (PGL5; <a href="/entry/614165">614165</a>), <a href="#22" class="mim-tip-reference" title="Welander, J., Garvin, S., Bohnmark, R., Isaksson, L., Wiseman, R. W., Soderkvist, P., Gimm, O. <strong>Germline SDHA mutation detected by next-generation sequencing in a young index patient with large paraganglioma.</strong> J. Clin. Endocr. Metab. 98: E1379-E1380, 2013. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23750034/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23750034</a>] [<a href="https://doi.org/10.1210/jc.2013-1963" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23750034">Welander et al. (2013)</a> identified a heterozygous germline c.223C-T transition in the SDHA gene, resulting in an arg75-to-ter (R75X) substitution. Tumor tissue showed absence of SDHA and SDHB (<a href="/entry/185470">185470</a>) immunostaining. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23750034" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1553999752 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1553999752;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1553999752" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1553999752" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000521022 OR RCV001063769 OR RCV001363197 OR RCV001799673 OR RCV002384004 OR RCV003152716" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000521022, RCV001063769, RCV001363197, RCV001799673, RCV002384004, RCV003152716" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000521022...</a>
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<p>In 2 adult sisters with neurodegeneration with ataxia and late-onset optic atrophy (NDAXOA; <a href="/entry/619259">619259</a>), who were originally reported by <a href="#19" class="mim-tip-reference" title="Taylor, R. W., Birch-Machin, M. A., Schaefer, J., Taylor, L., Shakir, R., Ackrell, B. A. C., Cochran, B., Bindoff, L. A., Jackson, M. J., Griffiths, P., Turnbull, D. M. <strong>Deficiency of complex II of the mitochondrial respiratory chain in late-onset optic atrophy and ataxia.</strong> Ann. Neurol. 39: 224-232, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8967754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8967754</a>] [<a href="https://doi.org/10.1002/ana.410390212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8967754">Taylor et al. (1996)</a>, <a href="#2" class="mim-tip-reference" title="Birch-Machin, M. A., Taylor, R. W., Cochran, B., Ackrell, B. A. C., Turnbull, D. M. <strong>Late-onset optic atrophy, ataxia, and myopathy associated with a mutation of a complex II gene.</strong> Ann. Neurol. 48: 330-335, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10976639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10976639</a>]" pmid="10976639">Birch-Machin et al. (2000)</a> identified a heterozygous c.1375C-T transition in the SDHA gene, resulting in an arg408-to-cys (R408C) substitution in a highly conserved region (this numbering is equivalent to R451C; see <a href="#6" class="mim-tip-reference" title="Courage, C., Jackson, C. B., Hahn, D., Euro, L., Nuoffer, J.-M., Gallati, S., Schaller, A. <strong>SDHA mutation with dominant transmission results in complex II deficiency with ocular, cardiac, and neurologic involvement.</strong> Am. J. Med. Genet. 173A: 225-230, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27683074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27683074</a>] [<a href="https://doi.org/10.1002/ajmg.a.37986" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27683074">Courage et al., 2017</a>). The mutation, which was found by direct sequencing, was not found in an unaffected sister or in 80 control samples. In vitro functional expression studies in E. coli showed almost no mitochondrial complex II or SDH activity compared to controls; there was decreased protein expression at the membrane. The evidence suggested that the mutation interfered with association of the FAD cofactor. Patient myoblasts showed normal membrane content of SDHA immunoreactive protein, but complex II and SDH activity were 50% of normal values. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8967754+10976639+27683074" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 affected members of a 2-generation family with NDAXOA, <a href="#6" class="mim-tip-reference" title="Courage, C., Jackson, C. B., Hahn, D., Euro, L., Nuoffer, J.-M., Gallati, S., Schaller, A. <strong>SDHA mutation with dominant transmission results in complex II deficiency with ocular, cardiac, and neurologic involvement.</strong> Am. J. Med. Genet. 173A: 225-230, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27683074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27683074</a>] [<a href="https://doi.org/10.1002/ajmg.a.37986" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27683074">Courage et al. (2017)</a> identified a heterozygous c.1351C-T transition in exon 10 of the SDHA gene, resulting in an arg451-to-cys (R451C) substitution. The authors noted that this is the same mutation as that identified by <a href="#2" class="mim-tip-reference" title="Birch-Machin, M. A., Taylor, R. W., Cochran, B., Ackrell, B. A. C., Turnbull, D. M. <strong>Late-onset optic atrophy, ataxia, and myopathy associated with a mutation of a complex II gene.</strong> Ann. Neurol. 48: 330-335, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10976639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10976639</a>]" pmid="10976639">Birch-Machin et al. (2000)</a>. Molecular modeling predicted that the mutation interfered with succinate binding, causing a loss of succinate dehydrogenase activity. Functional studies of the variant were not performed, but patient cells showed about a 50% decrease in complex II activity. The patients in this family also developed cardiomyopathy, including an infant who died at 7 months of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10976639+27683074" 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="#DiMauro1998" class="mim-tip-reference" title="DiMauro, S., Schon, E. A. <strong>Nuclear power and mitochondrial disease.</strong> Nature Genet. 19: 214-215, 1998.">DiMauro and Schon (1998)</a>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22972948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22972948</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22972948[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=22972948" 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/10.1136/jmedgenet-2012-101146" target="_blank">Full Text</a>]
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Birch-Machin, M. A., Taylor, R. W., Cochran, B., Ackrell, B. A. C., Turnbull, D. M.
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<strong>Late-onset optic atrophy, ataxia, and myopathy associated with a mutation of a complex II gene.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10976639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10976639</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10976639" 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/s0387-7604(12)80349-4" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550341</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7550341" 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/ng1095-144" target="_blank">Full Text</a>]
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Burnichon, N,, Briere, J.-J., Libe, R., Vescovo, L., Riviere, J., Tissier, F., Jouanno, E., Jeunemaitre, X., Benit, P., Tzagoloff, A., Rustin, P., Bertherat, J., Favier, J., Gimenez-Roqueplo, A.-P.
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<strong>SDHA is a tumor suppressor gene causing paraganglioma.</strong>
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Hum. Molec. Genet. 19: 3011-3020, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20484225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20484225</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20484225[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=20484225" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddq206" target="_blank">Full Text</a>]
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<a id="Courage2017" class="mim-anchor"></a>
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Courage, C., Jackson, C. B., Hahn, D., Euro, L., Nuoffer, J.-M., Gallati, S., Schaller, A.
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<strong>SDHA mutation with dominant transmission results in complex II deficiency with ocular, cardiac, and neurologic involvement.</strong>
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Am. J. Med. Genet. 173A: 225-230, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27683074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27683074</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27683074" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.37986" target="_blank">Full Text</a>]
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Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27626380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27626380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27626380[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=27626380" 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/nature19356" target="_blank">Full Text</a>]
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DiMauro, S., Schon, E. A.
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<strong>Nuclear power and mitochondrial disease.</strong>
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Nature Genet. 19: 214-215, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9662387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9662387</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9662387" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/oxfordjournals.jbchem.a124497" target="_blank">Full Text</a>]
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Korpershoek, E., Favier, J., Gaal, J., Burnichon, N., van Gessel, B., Oudijk, L., Badoual, C., Gadessaud, N., Venisse, A., Bayley, J.-P., van Dooren, M. F., de Herder, W. W., Tissier, F., Plouin, P.-F., van Nederveen, F. H., Dinjens, W. N. M., Gimenez-Roqueplo, A.-P., de Krijger, R. R.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21752896/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21752896</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21752896" 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/10.1210/jc.2011-1043" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20551992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20551992</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20551992" 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/ejhg.2010.83" target="_blank">Full Text</a>]
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Mills, E. L., Pierce, K. A., Jedrychowski, M. P., Garrity, R., Winther, S., Vidoni, S., Yoneshiro, T., Spinelli, J. B., Lu, G. Z., Kazak, L., Banks, A. S., Haigis, M. C., Kajimura, S., Murphy, M. P., Gygi, S. P., Clish, C. B, Chouchani, E. T.
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[<a href="https://doi.org/10.1038/s41586-018-0353-2" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0005-2728(94)90203-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ymgme.2006.05.003" target="_blank">Full Text</a>]
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<p class="mim-text-font">
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Parfait, B., Chretien, D., Rotig, A., Marsac, C., Munnich, A., Rustin, P.
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<strong>Compound heterozygous mutations in the flavoprotein gene of the respiratory chain complex II in a patient with Leigh syndrome.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10746566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10746566</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10746566" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s004390051033" target="_blank">Full Text</a>]
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<a id="Spinelli2021" class="mim-anchor"></a>
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Spinelli, J. B., Rosen, P. C., Sprenger, H.-G., Puszynska, A. M., Mann, J. L., Roessler, J. M., Cangelosi, A. L., Henne, A., Condon, K. J., Zhang, T., Kunchok, T., Lewis, C. A., Chandel, N. S., Sabatini, D. M.
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<strong>Fumarate is a terminal electron acceptor in the mammalian electron transport chain.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34855504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34855504</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34855504[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=34855504" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.abi7495" target="_blank">Full Text</a>]
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<a id="Steinmetz2002" class="mim-anchor"></a>
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Steinmetz, L. M., Scharfe, C., Deutschbauer, A. M., Mokranjac, D., Herman, Z. S., Jones, T., Chu, A. M., Giaever, G., Prokisch, H., Oefner, P. J., Davis, R. W.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12134146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12134146</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12134146" 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/ng929" target="_blank">Full Text</a>]
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Taylor, R. W., Birch-Machin, M. A., Schaefer, J., Taylor, L., Shakir, R., Ackrell, B. A. C., Cochran, B., Bindoff, L. A., Jackson, M. J., Griffiths, P., Turnbull, D. M.
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Ann. Neurol. 39: 224-232, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8967754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8967754</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8967754" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.410390212" target="_blank">Full Text</a>]
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<a id="Van Coster2003" class="mim-anchor"></a>
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Van Coster, R., Seneca, S., Smet, J., Van Hecke, R., Gerlo, E., Devreese, B., Van Beeumen, J., Leroy, J. G., De Meirleir, L., Lissens, W.
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<strong>Homozygous gly555-to-glu mutation in the nuclear-encoded 70 kDa flavoprotein gene causes instability of the respiratory chain complex II.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12794685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12794685</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12794685" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.10202" target="_blank">Full Text</a>]
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Wallace, D. C.
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<strong>Mitochondrial diseases in man and mouse.</strong>
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Science 283: 1482-1488, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10066162/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10066162</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10066162" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.283.5407.1482" target="_blank">Full Text</a>]
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Welander, J., Garvin, S., Bohnmark, R., Isaksson, L., Wiseman, R. W., Soderkvist, P., Gimm, O.
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<strong>Germline SDHA mutation detected by next-generation sequencing in a young index patient with large paraganglioma.</strong>
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J. Clin. Endocr. Metab. 98: E1379-E1380, 2013. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23750034/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23750034</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23750034" 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/10.1210/jc.2013-1963" target="_blank">Full Text</a>]
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Ada Hamosh - updated : 11/28/2022
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 04/05/2021<br>Ada Hamosh - updated : 09/21/2018<br>Ada Hamosh - updated : 02/21/2017<br>Cassandra L. Kniffin - updated : 9/21/2015<br>Cassandra L. Kniffin - updated : 1/14/2013<br>Cassandra L. Kniffin - updated : 8/15/2011<br>Marla J. F. O'Neill - updated : 11/9/2010<br>Cassandra L. Kniffin - reorganized : 9/21/2005<br>Cassandra L. Kniffin - updated : 8/30/2005<br>Victor A. McKusick - updated : 6/23/2003<br>Victor A. McKusick - updated : 9/12/2002<br>Victor A. McKusick - updated : 3/8/2000<br>Victor A. McKusick - updated : 3/3/1998
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Creation Date:
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<span class="mim-text-font">
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Victor A. McKusick : 10/17/1995
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mgross : 04/18/2024
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carol : 10/17/2023<br>alopez : 11/28/2022<br>carol : 04/09/2021<br>carol : 04/08/2021<br>ckniffin : 04/05/2021<br>carol : 01/28/2021<br>alopez : 09/21/2018<br>carol : 01/31/2018<br>carol : 04/27/2017<br>alopez : 02/21/2017<br>carol : 09/08/2016<br>alopez : 09/07/2016<br>carol : 09/24/2015<br>ckniffin : 9/21/2015<br>carol : 8/18/2015<br>mcolton : 8/12/2015<br>alopez : 2/1/2013<br>ckniffin : 1/14/2013<br>wwang : 8/16/2011<br>ckniffin : 8/15/2011<br>wwang : 11/16/2010<br>terry : 11/9/2010<br>alopez : 9/16/2009<br>carol : 9/21/2005<br>ckniffin : 8/30/2005<br>cwells : 6/24/2003<br>terry : 6/23/2003<br>tkritzer : 12/10/2002<br>terry : 12/6/2002<br>carol : 9/19/2002<br>tkritzer : 9/12/2002<br>tkritzer : 9/12/2002<br>alopez : 6/4/2001<br>mcapotos : 4/6/2000<br>mcapotos : 4/4/2000<br>mcapotos : 4/4/2000<br>terry : 3/8/2000<br>carol : 6/5/1998<br>alopez : 3/3/1998<br>alopez : 3/3/1998<br>terry : 3/3/1998<br>mark : 5/19/1997<br>mark : 12/4/1995<br>mark : 12/4/1995<br>mimadm : 11/3/1995<br>mark : 10/17/1995
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<strong>*</strong> 600857
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<h3>
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SUCCINATE DEHYDROGENASE COMPLEX, FLAVOPROTEIN SUBUNIT A; SDHA
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<em>Alternative titles; symbols</em>
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SUCCINATE DEHYDROGENASE COMPLEX, SUBUNIT A, FLAVOPROTEIN<br />
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SUCCINATE DEHYDROGENASE 1, S. CEREVISIAE, HOMOLOG OF<br />
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SDH1, HOMOLOG OF
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<strong><em>HGNC Approved Gene Symbol: SDHA</em></strong>
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<strong>
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<em>
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Cytogenetic location: 5p15.33
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Genomic coordinates <span class="small">(GRCh38)</span> : 5:218,320-268,746 </span>
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</em>
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</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
5p15.33
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Cardiomyopathy, dilated, 1GG
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
613642
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Mitochondrial complex II deficiency, nuclear type 1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
252011
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Neurodegeneration with ataxia and late-onset optic atrophy
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
619259
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Pheochromocytoma/paraganglioma syndrome 5
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
614165
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Complex II of the mitochondrial respiratory chain, also known as succinate dehydrogenase or succinate:ubiquinone oxidoreductase (EC 1.3.5.1), consists of 4 nuclear-encoded polypeptides. In order of decreasing molecular mass, these are the flavoprotein subunit (SDHA), the iron sulfur protein subunit (SDHB; 185470), and the integral membrane protein subunits SDHC (602413) and SDHD (602690) (summary by Hirawake et al., 1994). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Hirawake et al. (1994) isolated a cDNA corresponding to the flavoprotein subunit of SDH from a human liver cDNA library. The deduced 621-amino acid protein has a molecular mass of approximately 68 kD and shows high homology to the bovine heart flavoprotein subunit. </p><p>Morris et al. (1994) cloned and sequenced the flavoprotein subunit of human heart SDH. </p><p>Burnichon et al. (2010) determined that the SDHA gene is highly polymorphic. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>SDH Complex Function</em></strong></p><p>
|
|
Mills et al. (2018) showed that substantial and selective accumulation of the tricarboxylic acid cycle intermediate succinate is a metabolic signature of adipose tissue thermogenesis upon activation by exposure to cold. Succinate accumulation occurs independently of adrenergic signaling, and is sufficient to elevate thermogenic respiration in brown adipocytes. Selective accumulation of succinate may be driven by a capacity of brown adipocytes to sequester elevated circulating succinate. Furthermore, brown adipose tissue thermogenesis can be initiated by systemic administration of succinate in mice. Succinate from the extracellular milieu is rapidly metabolized by brown adipocytes, and its oxidation by succinate dehydrogenase is required for activation of thermogenesis. Mills et al. (2018) identified a mechanism whereby succinate dehydrogenase-mediated oxidation of succinate initiates production of reactive oxygen species, and drives thermogenic respiration, whereas inhibition of succinate dehydrogenase suppresses thermogenesis. Finally, Mills et al. (2018) showed that pharmacologic elevation of circulating succinate drives UCP1 (113730)-dependent thermogenesis by brown adipose tissue in vivo, which stimulates robust protection against diet-induced obesity and improves glucose tolerance. </p><p>In mammalian cells, Spinelli et al. (2021) found that when oxygen reduction is impeded, mitochondrial complex I and dihydroorotate dehydrogenase (DHODH; 126064) can still deposit electrons into the electron transport chain because the accumulation of ubiquinol drives the succinate dehydrogenase complex in reverse to enable electron deposition onto fumarate. Fumarate sustains DHODH and complex I activities by acting as the terminal electron acceptor, maintaining mitochondrial function under oxygen limitation. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>By fluorescence in situ hybridization, Bourgeron et al. (1995) demonstrated that the flavoprotein subunit gene is duplicated in the human genome, present on chromosomes 3q29 and 5p15, with only the gene on chromosome 5 expressed in human/hamster somatic cell hybrids. The gene on chromosome 3q29 is a pseudogene. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Mitochondrial Complex II Deficiency, Nuclear Type 1</em></strong></p><p>
|
|
In 2 sibs with mitochondrial complex II deficiency nuclear type 1 (MC2DN1; 252011) presenting as Leigh syndrome (see 256000), Bourgeron et al. (1995) identified a homozygous mutation in the SHDA gene (R554W; 600857.0001). Bourgeron et al. (1995) claimed that this was the first report of a nuclear gene mutation causing a mitochondrial respiratory chain deficiency in humans. </p><p>In a patient with MC2DN1 manifesting as Leigh syndrome, Parfait et al. (2000) identified compound heterozygous 2 mutations in the SDHA gene (A524V, 600857.0002; M1L, 600857.0003). </p><p>In a female infant who died at 5.5 months of age following a respiratory infection and was found to have MC2DN1, Van Coster et al. (2003) identified homozygosity for a missense mutation in the SDHA gene (G555E; 600857.0004). The authors noted that the patient died in infancy before signs of Leigh syndrome could develop. </p><p>Pagnamenta et al. (2006) reported a 10-year-old Palestinian boy with MC2DN1 manifest as Leigh syndrome in whom they identified homozygosity for the G555E mutation in the SDHA gene. Pagnamenta et al. (2006) noted that the patient previously reported by Van Coster et al. (2003) with the G555E mutation was also of Middle Eastern origin, suggesting the possibility of an ancestral mutation. </p><p><strong><em>Dilated Cardiomyopathy 1GG</em></strong></p><p>
|
|
In 15 Bedouin patients from a single tribe with neonatal dilated cardiomyopathy (CMD1GG; 613642), Levitas et al. (2010) identified homozygosity for the G555E mutation in the SDHA gene. The patients all had a normal neuromuscular examination at presentation and follow-up, and psychomotor development was appropriate for age. Brain MRI was performed in 2 patients and showed no focal lesions. </p><p><strong><em>Pheochromocytoma/Paraganglioma Syndrome 5</em></strong></p><p>
|
|
In a woman with a catecholamine-secreting extraadrenal paraganglioma (PPGL5; 614165), Burnichon et al. (2010) identified a heterozygous germline mutation in the SDHA gene (R589W; 600857.0005). Tumor tissue showed loss of heterozygosity (LOH) at the SDHA locus. In vitro functional expression studies in the yeast homolog showed that the mutation resulted in a loss of SDH activity and rendered the mutant SDHA protein more susceptible to proteolysis. Studies of tumor tissue from the patient showed lack of SDHA and SDHB (185470) expression. Transcriptome analysis of the patient's tumor showed a similar pattern as that of other SDH-subunit mutated paraganglioma tumors, including stabilization of HIF1A (603348), consistent with activation of a pseudohypoxic pathway and angiogenesis. The findings indicated that SDHA, like other SDH subunits, can act as a tumor suppressor gene. Analysis of a large series of paragangliomas and pheochromocytomas found LOH at the SDHA locus in only 9 (4.5%) of 202 tumors, suggesting that it is an infrequent event. </p><p>Korpershoek et al. (2011) found that 7 of 316 pheochromocytomas and paragangliomas, including the SDHA-mutated paraganglioma described by Burnichon et al. (2010), were negative for SDHA immunostaining. All patients were found to carry a heterozygous mutation in the SDHA gene (600857.0005; 600857.0008-600857.0009), and all tumor tissue showed LOH for the wildtype SDHA allele. None of the patients had a family history of the disorder. All tumors were also negative for SDHB immunostaining, suggesting that impaired complex II formation results in SDHB degradation. The findings established SDHA as a tumor-suppressor gene. </p><p><strong><em>Neurodegeneration with Ataxia and Late-Onset Optic Atrophy</em></strong></p><p>
|
|
In 2 adult sisters with neurodegeneration with ataxia and late-onset optic atrophy (NDAXOA; 619259), who were originally reported by Taylor et al. (1996), Birch-Machin et al. (2000) identified a heterozygous missense mutation in the SDHA gene (R451C; 600857.0011). The mutation, which was found by direct sequencing, was not found in an unaffected sister or in 80 control samples. In vitro functional expression studies in E. coli showed almost no mitochondrial complex II or SDH activity compared to controls; there was decreased protein expression at the membrane. The evidence suggested that the mutation interfered with association of the FAD cofactor. Patient myoblasts showed normal membrane content of SDHA immunoreactive protein, but complex II and SDH activity were 50% of normal values. </p><p>In 3 affected members of a 2-generation family with NDAXOA, Courage et al. (2017) identified a heterozygous R451C mutation in the SDHA gene. Molecular modeling predicted that the mutation interfered with succinate binding, causing a loss of succinate dehydrogenase activity. Functional studies of the variant were not performed, but patient cells showed about a 50% decrease in complex II activity. The patients in this family also developed cardiomyopathy, including an infant who died at 7 months of age. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human SDHA is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>History</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>High similarity between yeast and human mitochondria allows functional genomic study of S. cerevisiae to be used in identifying human genes involved in disease (Foury, 1997). A considerable number of heritable disorders had been attributed to defects in known nuclear-encoded mitochondrial proteins in humans. Many mitochondrial diseases remained unexplained, however, in part because only 40 to 60% of the presumed 700 to 1,000 proteins involved in mitochondrial function and biogenesis had been identified (Wallace, 1999). Steinmetz et al. (2002) applied a systematic functional screen using the preexisting whole-genome pool of yeast deletion mutants to identify mitochondrial proteins. A large number of measurements of strain fitness identified 466 genes whose deletions impaired mitochondrial respiration, 265 of which were new. The approach gave higher selection than other systematic approaches, including 5-fold greater selection than gene expression analysis. To apply these advantages to human disorders involving mitochondria, human orthologs were identified and linked to heritable diseases using genomic map positions. Steinmetz et al. (2002) identified 22 human mitochondria-related genes that give rise to disease and for which there was an associated quantitative deletion phenotype in yeast. They also identified new human candidate genes as the possible basis of mitochondria-related diseases, including spastic paraplegia-5A (270800), Friedreich ataxia-2 (FRDA2; 601992), and 2 forms of optic atrophy: OPA2 (311050) and OPA4 (605293). Deletion in the yeast homolog suggested genes as the basis of the human disorder. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>11 Selected Examples):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SDHA, ARG554TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs9809219,
|
|
|
|
|
|
gnomAD: rs9809219,
|
|
|
|
|
|
ClinVar: RCV000009281, RCV000456631, RCV000573113, RCV000790927, RCV001818148, RCV003315222, RCV003473060, RCV005031432
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs with complex II mitochondrial respiratory chain deficiency nuclear type 1 (MC2DN1; 252011) presenting as Leigh syndrome (see 256000), Bourgeron et al. (1995) demonstrated a 1684C-T transition in the succinate dehydrogenase flavoprotein subunit gene in a CpG dinucleotide, resulting in an arg554-to-trp (R554W) substitution in a conserved domain of the protein. Functional expression studies in an SDH-negative yeast strain transformed with the mutant R554W protein showed decreased catalytic activity (approximately 50% of controls). The mutation was absent from 120 controls. The sibs were originally described by Bourgeois et al. (1992). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SDHA, ALA524VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852767,
|
|
|
|
|
|
|
|
ClinVar: RCV000009282, RCV000520939, RCV000649458, RCV002399314, RCV003473061
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a girl with mitochondrial complex II deficiency nuclear type 1 (MC2DN1; 252011) presenting as Leigh syndrome (see 256000), Parfait et al. (2000) identified compound heterozygous mutations in the SDHA gene: a C-to-T transition, resulting in an ala524-to-val (A524V) substitution, and an A-to-C transversion, resulting in a met1-to-leu (M1L; 600857.0003) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SDHA, MET1LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1061517,
|
|
|
|
|
|
gnomAD: rs1061517,
|
|
|
|
|
|
ClinVar: RCV000009283, RCV001233940, RCV002415407, RCV003234897, RCV003450622
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the met1-to-leu (M1L) mutation in the SDHA gene that was found in compound heterozygous state in a patient with complex II deficiency nuclear type 1 (MC2DN1; 252011) by Parfait et al. (2000), see 600857.0002. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
CARDIOMYOPATHY, DILATED, 1GG, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SDHA, GLY555GLU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852768,
|
|
|
|
|
|
gnomAD: rs137852768,
|
|
|
|
|
|
ClinVar: RCV000009284, RCV000009286, RCV001221088
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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<div>
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<span class="mim-text-font">
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<p />
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<p><strong><em>Mitochondrial Complex II Deficiency, Nuclear Type 1</em></strong></p><p>
|
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In a patient with mitochondrial complex II deficiency nuclear type 1 (MC2DN1; 252011), born of first-cousin parents, Van Coster et al. (2003) identified a homozygous 1664G-A transition in exon 13 of the SDHA gene, resulting in a gly555-to-glu (G555E) substitution. The patient died at 5.5 months of age following a respiratory infection. Crossreacting material (CRM) for flavoprotein as well as iron-containing protein was decreased, and CRM for the entire complex II was reduced even more. The observation prompted speculation of a labile interaction between iron-containing protein and flavoprotein polypeptides and of a key role of the amino acid at position 555 in the interacting domain. The observation pointed to the fragile equilibrium of intermediate metabolism in infants with complex II deficiency. </p><p>In a 10-year-old boy with relatively mild Leigh syndrome and isolated deficiency of mitochondrial complex II and relatively mild Leigh syndrome, who was born of consanguineous Palestinian parents, Pagnamenta et al. (2006) identified homozygosity for the G555E mutation in the SDHA gene. The unaffected parents were heterozygous for the mutation, which was not found in 60 controls. The authors noted that the patient previously reported by Van Coster et al. (2003) with the G555E mutation was also of Middle Eastern origin, suggesting the possibility of an ancestral mutation. Pagnamenta et al. (2006) stated that both patients had comparable activities and stability of mitochondrial respiratory chain enzymes. Biochemical studies of cultured fibroblasts showed that the size of the band corresponding to the partially assembled complex II differed slightly between the 2 patients; however, their phenotypic variability remained unexplained. </p><p><strong><em>Dilated Cardiomyopathy 1GG</em></strong></p><p>
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|
In 15 Bedouin patients from a single tribe with neonatal dilated cardiomyopathy (CMD1GG; 613642), including 13 patients from 2 consanguineous families and 2 sporadic patients, Levitas et al. (2010) identified homozygosity for the G555E mutation in the SDHA gene. The patients all had a normal neuromuscular examination at presentation and follow-up, and psychomotor development was appropriate for age. Brain MRI was performed in 2 patients and showed no focal lesions. Levitas et al. (2010) noted that the unaffected father of 1 of the patients was also homozygous for the G555E mutation, and he had 3 sibs who had died at a young age due to cardiovascular failure. Evaluation of other subunits of complex II (SDHB, 185470; SDHD, 602690) and a candidate modifier gene (SDHAF1; 612848) showed no difference between the father, his affected son, and other Bedouin patients. The enzymatic activity of the father's complex II was decreased by 42% and was more similar to that of the other patients than to the heterozygous mother or controls. Levitas et al. (2010) stated that they did not have an explanation for the normal phenotype of the father. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 5</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SDHA, ARG589TRP
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<br />
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SNP: rs387906780,
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gnomAD: rs387906780,
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ClinVar: RCV000023042, RCV000554026, RCV000564186, RCV001799611, RCV003162258, RCV003473121
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a woman with a catecholamine-secreting extraadrenal paraganglioma (PPGL5; 614165), Burnichon et al. (2010) identified a heterozygous germline 1765C-T transition in the SDHA gene, resulting in an arg589-to-trp (R589W) substitution at a highly conserved residue. The mutation was not found in 740 control chromosomes. Tumor tissue showed loss of heterozygosity (LOH) at the SDHA locus. In vitro functional expression studies in the yeast homolog showed that the mutation resulted in a loss of SDH activity and rendered the mutant SDHA protein more susceptible to proteolysis. Studies of tumor tissue from the patient showed lack of SDHA and SDHB (185470) expression. Transcriptome analysis of the patient's tumor showed a similar pattern as that of other SDH-subunit mutated paraganglioma tumors, including stabilization of HIF1A (603348), consistent with activation of a pseudohypoxic pathway and angiogenesis. The findings indicated that SDHA, like other SDH subunits, can act as a tumor suppressor gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SDHA, THR508ILE
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<br />
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SNP: rs151266052,
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gnomAD: rs151266052,
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ClinVar: RCV000032785, RCV000232220, RCV000563852, RCV001719715, RCV001818204
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a boy with mitochondrial complex II deficiency nuclear type 1 (MC2DN1; 252011) manifest as cardiomyopathy and leukoencephalopathy, Alston et al. (2012) identified compound heterozygosity for 2 mutations in the SDHA gene: a 1523C-T transition in exon 11 resulting in a thr508-to-ile (T508I) substitution, and a 1526C-T transition in exon 11 resulting in a ser509-to-leu (S509L; 600857.0007) substitution. Both mutations occurred at highly conserved residues within the catalytic flavoprotein subunit of the complex. Each unaffected parent was heterozygous for 1 of the mutations. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 1</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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SDHA, SER509LEU
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<br />
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SNP: rs397514541,
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gnomAD: rs397514541,
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ClinVar: RCV000032786, RCV000695865, RCV004948142
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>For discussion of the ser509-to-leu (S509L) mutation in the SDHA gene that was found in compound heterozygous state in a patient with mitochondrial complex II deficiency nuclear type 1 (MC2DN1; 252011) by Alston et al. (2012), see 600857.0006. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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SDHA, ARG31TER
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<br />
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SNP: rs142441643,
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gnomAD: rs142441643,
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|
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ClinVar: RCV000131808, RCV000148026, RCV000170328, RCV000413945, RCV000627791, RCV000722034, RCV001089554, RCV001257553, RCV001762318, RCV001799624, RCV002478402, RCV003330507, RCV003335126, RCV003474779
|
|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 4 Dutch patients with paragangliomas (PPGL5; 614165), Korpershoek et al. (2011) identified a heterozygous germline c.91C-T transition (c.91C-T, NM_004168) in the SDHA gene, resulting in an arg31-to-ter (R31X) substitution. The mutation was found in 2 (0.3%) of 692 Dutch controls. All corresponding tumors showed loss of heterozygosity for SDHA and lack of SDHA and SDHB (185470) immunostaining. </p>
|
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</span>
|
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</div>
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<div>
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<br />
|
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
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<span class="mim-text-font">
|
|
|
|
SDHA, ARG585TRP
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<br />
|
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|
|
SNP: rs200397144,
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|
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|
|
|
gnomAD: rs200397144,
|
|
|
|
|
|
ClinVar: RCV000148027, RCV000163558, RCV000464783, RCV000762143, RCV000765834, RCV001824123, RCV003474794
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a French patient with paragangliomas (PGL5; 614165), Korpershoek et al. (2011) identified a heterozygous germline c.1753C-T transition (c.1753C-T, NM_004168) in the SDHA gene, resulting in an arg585-to-trp (R585W) substitution. The mutation was found in 1 (0.1%) of 972 Dutch controls. Tumor tissue showed loss of heterozygosity for SDHA and lack of SDHA and SDHB (185470) immunostaining. </p>
|
|
</span>
|
|
</div>
|
|
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|
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|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SDHA, ARG75TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs781764920,
|
|
|
|
|
|
gnomAD: rs781764920,
|
|
|
|
|
|
ClinVar: RCV000191050, RCV000481058, RCV000575496, RCV000684793, RCV002492875, RCV003474945
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 20-year-old woman with paragangliomas (PGL5; 614165), Welander et al. (2013) identified a heterozygous germline c.223C-T transition in the SDHA gene, resulting in an arg75-to-ter (R75X) substitution. Tumor tissue showed absence of SDHA and SDHB (185470) immunostaining. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 NEURODEGENERATION WITH ATAXIA AND LATE-ONSET OPTIC ATROPHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SDHA, ARG451CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1553999752,
|
|
|
|
|
|
|
|
ClinVar: RCV000521022, RCV001063769, RCV001363197, RCV001799673, RCV002384004, RCV003152716
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 adult sisters with neurodegeneration with ataxia and late-onset optic atrophy (NDAXOA; 619259), who were originally reported by Taylor et al. (1996), Birch-Machin et al. (2000) identified a heterozygous c.1375C-T transition in the SDHA gene, resulting in an arg408-to-cys (R408C) substitution in a highly conserved region (this numbering is equivalent to R451C; see Courage et al., 2017). The mutation, which was found by direct sequencing, was not found in an unaffected sister or in 80 control samples. In vitro functional expression studies in E. coli showed almost no mitochondrial complex II or SDH activity compared to controls; there was decreased protein expression at the membrane. The evidence suggested that the mutation interfered with association of the FAD cofactor. Patient myoblasts showed normal membrane content of SDHA immunoreactive protein, but complex II and SDH activity were 50% of normal values. </p><p>In 3 affected members of a 2-generation family with NDAXOA, Courage et al. (2017) identified a heterozygous c.1351C-T transition in exon 10 of the SDHA gene, resulting in an arg451-to-cys (R451C) substitution. The authors noted that this is the same mutation as that identified by Birch-Machin et al. (2000). Molecular modeling predicted that the mutation interfered with succinate binding, causing a loss of succinate dehydrogenase activity. Functional studies of the variant were not performed, but patient cells showed about a 50% decrease in complex II activity. The patients in this family also developed cardiomyopathy, including an infant who died at 7 months of age. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
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|
|
|
|
|
</div>
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<span class="mim-text-font">
|
|
DiMauro and Schon (1998)
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
|
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Alston, C. L., Davison, J. E., Meloni, F., van der Westhuizen, F. H., He, L., Hornig-Do, H.-T., Peet, A. C., Gissen, P., Goffrini, P., Ferrero, I., Wassmer, E., McFarland, R., Taylor, R. W.
|
|
<strong>Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency.</strong>
|
|
J. Med. Genet. 49: 569-577, 2012.
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|
|
[PubMed: 22972948]
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[Full Text: https://doi.org/10.1136/jmedgenet-2012-101146]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Birch-Machin, M. A., Taylor, R. W., Cochran, B., Ackrell, B. A. C., Turnbull, D. M.
|
|
<strong>Late-onset optic atrophy, ataxia, and myopathy associated with a mutation of a complex II gene.</strong>
|
|
Ann. Neurol. 48: 330-335, 2000.
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|
|
[PubMed: 10976639]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Bourgeois, M., Goutieres, F., Chretien, D., Rustin, P., Munnich, A., Aicardi, J.
|
|
<strong>Deficiency in complex II of the respiratory chain, presenting as a leukodystrophy in two sisters with Leigh syndrome.</strong>
|
|
Brain Dev. 14: 404-408, 1992.
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|
[PubMed: 1492653]
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[Full Text: https://doi.org/10.1016/s0387-7604(12)80349-4]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Bourgeron, T., Rustin, P., Chretien, D., Birch-Machin, M., Bourgeois, M., Viegas-Pequignot, E., Munnich, A., Rotig, A.
|
|
<strong>Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency.</strong>
|
|
Nature Genet. 11: 144-149, 1995.
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|
|
[PubMed: 7550341]
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[Full Text: https://doi.org/10.1038/ng1095-144]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Burnichon, N,, Briere, J.-J., Libe, R., Vescovo, L., Riviere, J., Tissier, F., Jouanno, E., Jeunemaitre, X., Benit, P., Tzagoloff, A., Rustin, P., Bertherat, J., Favier, J., Gimenez-Roqueplo, A.-P.
|
|
<strong>SDHA is a tumor suppressor gene causing paraganglioma.</strong>
|
|
Hum. Molec. Genet. 19: 3011-3020, 2010.
|
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|
|
[PubMed: 20484225]
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[Full Text: https://doi.org/10.1093/hmg/ddq206]
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</p>
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</li>
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<li>
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|
<p class="mim-text-font">
|
|
Courage, C., Jackson, C. B., Hahn, D., Euro, L., Nuoffer, J.-M., Gallati, S., Schaller, A.
|
|
<strong>SDHA mutation with dominant transmission results in complex II deficiency with ocular, cardiac, and neurologic involvement.</strong>
|
|
Am. J. Med. Genet. 173A: 225-230, 2017.
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|
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|
[PubMed: 27683074]
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[Full Text: https://doi.org/10.1002/ajmg.a.37986]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others.
|
|
<strong>High-throughput discovery of novel developmental phenotypes.</strong>
|
|
Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017.
|
|
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|
|
[PubMed: 27626380]
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|
|
[Full Text: https://doi.org/10.1038/nature19356]
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</p>
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</li>
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<li>
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|
<p class="mim-text-font">
|
|
DiMauro, S., Schon, E. A.
|
|
<strong>Nuclear power and mitochondrial disease.</strong>
|
|
Nature Genet. 19: 214-215, 1998.
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|
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|
|
[PubMed: 9662387]
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|
[Full Text: https://doi.org/10.1038/883]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Foury, F.
|
|
<strong>Human genetic diseases: a cross-talk between man and yeast.</strong>
|
|
Gene 195: 1-10, 1997.
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