3446 lines
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Entry
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- *615903 - COILED-COIL-HELIX-COILED-COIL-HELIX DOMAIN-CONTAINING PROTEIN 10; CHCHD10
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- OMIM
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<p>
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<span class="h4">*615903</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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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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<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 role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/615903">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li 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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<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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<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-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=ENSG00000250479;t=ENST00000484558" 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=400916" 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=615903" 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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<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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<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=ENSG00000250479;t=ENST00000484558" 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_001301339,NM_213720,NR_125755,NR_125756" 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_213720" 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=615903" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.proteinatlas.org/search/CHCHD10" 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/18147105,40806990,47497976,74731006,119580006,158260143,671744006" 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/Q8WYQ3" 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=400916" 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=ENSG00000250479;t=ENST00000484558" 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=CHCHD10" 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=CHCHD10" 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+400916" 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/CHCHD10" 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:400916" 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/400916" 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=chr22&hgg_gene=ENST00000484558.3&hgg_start=23765834&hgg_end=23767972&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:15559" 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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=615903[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=615903[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000250479" 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=CHCHD10" 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=CHCHD10" 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=CHCHD10" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=CHCHD10&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/PA162382225" 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:15559" 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/FBgn0051007.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:2143558" 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/CHCHD10#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:2143558" 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/400916/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=400916" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00007630;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-040426-1753" 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:400916" 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=CHCHD10&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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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 1222644009<br />
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">ICD+</a>
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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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615903
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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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COILED-COIL-HELIX-COILED-COIL-HELIX DOMAIN-CONTAINING PROTEIN 10; CHCHD10
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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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<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=CHCHD10" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">CHCHD10</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>
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Cytogenetic location: <a href="/geneMap/22/101?start=-3&limit=10&highlight=101">22q11.23</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr22:23765834-23767972&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'})">22:23,765,834-23,767,972</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
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<div style="margin-bottom: 10px;">
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=616209,615911,615048" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
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</th>
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<th>
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Phenotype <br /> MIM number
|
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</th>
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<th>
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Inheritance
|
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</th>
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<th>
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Phenotype <br /> mapping key
|
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="3">
|
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<span class="mim-font">
|
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<a href="/geneMap/22/101?start=-3&limit=10&highlight=101">
|
|
22q11.23
|
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</a>
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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?Myopathy, isolated mitochondrial, autosomal dominant
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<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
|
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<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
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</span>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<a href="/entry/616209"> 616209 </a>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<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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<tr>
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<td>
|
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<span class="mim-font">
|
|
Frontotemporal dementia and/or amyotrophic lateral sclerosis 2
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/615911"> 615911 </a>
|
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|
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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="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
|
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<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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<tr>
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<td>
|
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<span class="mim-font">
|
|
Spinal muscular atrophy, Jokela type
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/615048"> 615048 </a>
|
|
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
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</span>
|
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</td>
|
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
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<p>CHCHD10 is a relatively small protein of the mitochondrial intermembrane space that is enriched at cristae junctions. It is predicted to be involved in oxidative phosphorylation or in maintenance of cristae morphology (<a href="#2" class="mim-tip-reference" title="Bannwarth, S., Ait-El-Mkadem, S., Chaussenot, A., Genin, E. C., Lacas-Gervais, S., Fragaki, K., Berg-Alonso, L., Kageyama, Y., Serre, V., Moore, D. G., Verschueren, A., Rouzier, C., and 11 others. <strong>A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement.</strong> Brain 137: 2329-2345, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24934289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24934289</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24934289[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/brain/awu138" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24934289">Bannwarth et al., 2014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24934289" 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 whole-exome sequencing, <a href="#2" class="mim-tip-reference" title="Bannwarth, S., Ait-El-Mkadem, S., Chaussenot, A., Genin, E. C., Lacas-Gervais, S., Fragaki, K., Berg-Alonso, L., Kageyama, Y., Serre, V., Moore, D. G., Verschueren, A., Rouzier, C., and 11 others. <strong>A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement.</strong> Brain 137: 2329-2345, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24934289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24934289</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24934289[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/brain/awu138" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24934289">Bannwarth et al. (2014)</a> identified the CHCHD10 gene. The deduced protein has a nonstructured N-terminal region, followed by a highly hydrophobic helix and a C-terminal CHCH domain characterized by a Cx(9)C motif and 2 additional cysteines; the 4 cysteine residues together are predicted to form 2 disulfide bonds. Western blot analysis of 9 human tissues detected ubiquitous CHCHD10 expression, with highest expression in heart and liver and lowest expression in spleen. Immunohistochemical and immunogold electron microscopy of HeLa cells localized CHCHD10 to mitochondria, where it was enriched at cristae junctions. Protease treatment and differential extraction of HeLa cell mitochondria revealed that CHCHD10 is a soluble protein of the intermembrane space. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24934289" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Ajroud-Driss, S., Fecto, F., Ajroud, K., Lalani, I., Calvo, S. E., Mootha, V. K., Deng, H.-X., Siddique, N., Tahmoush, A. J., Heiman-Patterson, T. D., Siddique, T. <strong>Mutation in the novel nuclear-encoded mitochondrial protein CHCHD10 in a family with autosomal dominant mitochondrial myopathy.</strong> Neurogenetics 16: 1-9, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25193783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25193783</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25193783[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/10.1007/s10048-014-0421-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25193783">Ajroud-Driss et al. (2015)</a> found that the CHCHD10 gene is highly expressed in human skeletal muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25193783" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By immunoblot analysis, <a href="#14" class="mim-tip-reference" title="Xiao, Y., Zhang, J., Shu, X., Bai, L., Xu, W., Wang, A., Chen, A., Tu, W. Y., Wang, J., Zhang, K., Luo, B., Shen, C. <strong>Loss of mitochondrial protein CHCHD10 in skeletal muscle causes neuromuscular junction impairment.</strong> Hum. Molec. Genet. 29: 1784-1796, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31261376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31261376</a>] [<a href="https://doi.org/10.1093/hmg/ddz154" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31261376">Xiao et al. (2020)</a> showed that Chchd10 was highly expressed in mouse skeletal muscle, whereas expression was low in spinal cord and sciatic nerve. In skeletal muscle, Chchd10 expression gradually increased after birth and peaked after 2 weeks. Further analysis revealed that Chchd10 expression was enriched at the postsynapse of mouse neuromuscular junction (NMJ), a tripartite synapse consisting of muscle fibers, Schwann cells, and motoneuron terminals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31261376" 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="#1" class="mim-tip-reference" title="Ajroud-Driss, S., Fecto, F., Ajroud, K., Lalani, I., Calvo, S. E., Mootha, V. K., Deng, H.-X., Siddique, N., Tahmoush, A. J., Heiman-Patterson, T. D., Siddique, T. <strong>Mutation in the novel nuclear-encoded mitochondrial protein CHCHD10 in a family with autosomal dominant mitochondrial myopathy.</strong> Neurogenetics 16: 1-9, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25193783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25193783</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25193783[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/10.1007/s10048-014-0421-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25193783">Ajroud-Driss et al. (2015)</a> reported that the CHCHD10 gene contains 4 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25193783" 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="#3" class="mim-tip-reference" title="Hartz, P. A. <strong>Personal Communication.</strong> Baltimore, Md. 7/24/2014."None>Hartz (2014)</a> mapped the CHCHD10 gene to chromosome 22q11.23 based on an alignment of the CHCHD10 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=BC065232" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">BC065232</a>) with the genomic sequence (GRCh37).</p>
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<p><strong><em>Frontotemporal Dementia and/or Amyotrophic Lateral Sclerosis-2, Autosomal Dominant</em></strong></p><p>
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In 8 affected members of a large French family with autosomal dominant frontotemporal dementia and/or amyotrophic lateral sclerosis-2 (FTDALS2; <a href="/entry/615911">615911</a>), <a href="#2" class="mim-tip-reference" title="Bannwarth, S., Ait-El-Mkadem, S., Chaussenot, A., Genin, E. C., Lacas-Gervais, S., Fragaki, K., Berg-Alonso, L., Kageyama, Y., Serre, V., Moore, D. G., Verschueren, A., Rouzier, C., and 11 others. <strong>A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement.</strong> Brain 137: 2329-2345, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24934289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24934289</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24934289[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/brain/awu138" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24934289">Bannwarth et al. (2014)</a> identified a heterozygous missense mutation in the CHCHD10 gene (S59L; <a href="#0001">615903.0001</a>). The mutation was found by whole-exome sequencing and segregated with the disorder in the family. Screening of the CHCHD10 gene in 21 additional families with a similar disorder identified the same heterozygous mutation in 1 proband of Spanish descent. Overexpression of the mutant protein in HeLa cells led to fragmentation of the mitochondrial network as well as major ultrastructural abnormalities, similar to those observed in patient cells. The findings implicated a role for dysfunctional mitochondria in the pathogenesis of late-onset frontotemporal dementia with motor neuron disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24934289" 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>Among 4,365 ALS patients and 1,832 controls from 7 different countries who underwent sequencing of the CHCHD10 gene, <a href="#9" class="mim-tip-reference" title="Project MinE ALS Sequencing Consortium. <strong>CHCHD10 variants in amyotrophic lateral sclerosis: Where is the evidence?</strong> Ann. Neurol. 84: 110-116, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30014597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30014597</a>] [<a href="https://doi.org/10.1002/ana.25273" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30014597">Project MinE ALS Sequencing Consortium (2018)</a> found no significantly increased disease-associated mutation burden, suggesting that mutations in the CHCHD10 gene are rare in typical ALS. Three ALS-specific variants were identified in 5 unrelated patients. One woman with ALS without dementia and no family history of the disease carried a heterozygous R11G variant. Three additional unrelated patients, 1 Dutch and 2 American, carried a heterozygous R15L variant (<a href="#0002">615903.0002</a>); 2 had a positive family history whereas the other did not. One of these patients had been reported by <a href="#5" class="mim-tip-reference" title="Johnson, J. O., Glynn, S. M., Gibbs, J. R., Nalls, M. A., Sabatelli, M., Restagno, G., Drory, V. E., Chio, A., Rogaeva, E., Traynor, B. J. <strong>Mutations in the CHCHD10 gene are a common cause of familial amyotrophic lateral sclerosis. (Letter)</strong> Brain 137: e311, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25261972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25261972</a>] [<a href="https://doi.org/10.1093/brain/awu265" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25261972">Johnson et al. (2014)</a>. Finally, a Belgian patient carried a heterozygous P80L variant. The phenotype in some of these patients was atypical for ALS and included myopathic features and deafness. S59L was not found in either patients or controls. Functional studies of the variants and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25261972+30014597" 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>Spinal Muscular Atrophy, Jokela Type</em></strong></p><p>
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In 55 patients from 17 Finnish families with the Jokela type of spinal muscular atrophy (SMAJ; <a href="/entry/615048">615048</a>), including the original families reported by <a href="#6" class="mim-tip-reference" title="Jokela, M., Penttila, S., Huovinen, S., Hackman, P., Maija Saukkonen, A., Toivanen, J., Udd, B. <strong>Late-onset lower motor neuronopathy: a new autosomal dominant disorder.</strong> Neurology 77: 334-340, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21715705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21715705</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3182267b71" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21715705">Jokela et al. (2011)</a> and a Finnish patient reported by <a href="#7" class="mim-tip-reference" title="Muller, K., Andersen, P. M., Hubers, A., Marroquin, N., Volk, A. E., Danzer, K. M., Meitinger, T., Ludolph, A. C., Strom, T. M., Weishaupt, J. H. <strong>Two novel mutations in conserved codons indicate that CHCHD10 is a gene associated with motor neuron disease. (Letter)</strong> Brain 137: e309, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25113787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25113787</a>] [<a href="https://doi.org/10.1093/brain/awu227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25113787">Muller et al. (2014)</a>, <a href="#8" class="mim-tip-reference" title="Penttila, S., Jokela, M., Bouquin, H., Saukkonen, A. M., Toivanen, J., Udd, B. <strong>Late onset spinal motor neuronopathy is caused by mutation in CHCHD10.</strong> Ann. Neurol. 77: 163-172, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25428574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25428574</a>] [<a href="https://doi.org/10.1002/ana.24319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25428574">Penttila et al. (2015)</a> identified the same heterozygous missense mutation in the CHCHD10 gene (G66V; <a href="#0003">615903.0003</a>). The mutation, which was found by linkage analysis and whole-genome sequencing, segregated with the disorder in all families. Haplotype analysis indicated a founder effect. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21715705+25428574+25113787" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Mitochondrial Myopathy, Isolated, Autosomal Dominant</em></strong></p><p>
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In all affected individuals in a 5-generation family of Puerto Rican descent with autosomal dominant isolated mitochondrial myopathy (IMMD; <a href="/entry/616209">616209</a>) originally reported by <a href="#4" class="mim-tip-reference" title="Heiman-Patterson, T. D., Argov, Z., Chavin, J. M., Kalman, B., Alder, H., DiMauro, S., Bank, W., Tahmoush, A. J. <strong>Biochemical and genetic studies in a family with mitochondrial myopathy.</strong> Muscle Nerve 20: 1219-1224, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9324076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9324076</a>] [<a href="https://doi.org/10.1002/(sici)1097-4598(199710)20:10<1219::aid-mus2>3.0.co;2-f" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9324076">Heiman-Patterson et al. (1997)</a>, <a href="#1" class="mim-tip-reference" title="Ajroud-Driss, S., Fecto, F., Ajroud, K., Lalani, I., Calvo, S. E., Mootha, V. K., Deng, H.-X., Siddique, N., Tahmoush, A. J., Heiman-Patterson, T. D., Siddique, T. <strong>Mutation in the novel nuclear-encoded mitochondrial protein CHCHD10 in a family with autosomal dominant mitochondrial myopathy.</strong> Neurogenetics 16: 1-9, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25193783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25193783</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25193783[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/10.1007/s10048-014-0421-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25193783">Ajroud-Driss et al. (2015)</a> identified a heterozygous missense mutation in the CHCHD10 gene (R15S/G58R; <a href="#0004">615903.0004</a>). The mutation, which was found by linkage analysis and candidate gene sequencing, segregated with the disorder in the family. In vitro studies showed that mitochondrial localization of the variant protein was similar to control. Cells transfected with the G58R mutation or the R15S/G58R mutants showed fragmentation of the mitochondria compared to wildtype or cells transfected only with R15S. The findings suggested that the R15S variant may not be pathogenic. <a href="#1" class="mim-tip-reference" title="Ajroud-Driss, S., Fecto, F., Ajroud, K., Lalani, I., Calvo, S. E., Mootha, V. K., Deng, H.-X., Siddique, N., Tahmoush, A. J., Heiman-Patterson, T. D., Siddique, T. <strong>Mutation in the novel nuclear-encoded mitochondrial protein CHCHD10 in a family with autosomal dominant mitochondrial myopathy.</strong> Neurogenetics 16: 1-9, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25193783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25193783</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25193783[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/10.1007/s10048-014-0421-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25193783">Ajroud-Driss et al. (2015)</a> noted that the G58R variant is adjacent to a mutation (S59L; <a href="#0001">615903.0001</a>) identified in a large family with a different neurologic disease, FTDALS2, and concluded that multiple phenotypes can result from defects in tissues that are highly dependent on oxidative phosphorylation, including muscle and nervous system tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25193783+9324076" 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 mother and her 2 sons (family UK) with IMMD, <a href="#11" class="mim-tip-reference" title="Shammas, M. K., Huang, X., Wu, B. P., Fessler, E., Song, I. Y., Randolph, N. P., Li, Y., Bleck, C. K., Springer, D. A., Fratter, C., Barbosa, I. A., Powers, A. F., Quiros, P. M., Lopez-Otin, C., Jae, L. T., Poulton, J., Narendra, D. P. <strong>OMA1 mediates local and global stress responses against protein misfolding in CHCHD10 mitochondrial myopathy.</strong> J. Clin. Invest. 132: e157504, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35700042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35700042</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35700042[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/10.1172/JCI157504" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35700042">Shammas et al. (2022)</a> identified a heterozygous missense mutation in the CHCHD10 gene (G58R; <a href="#0005">615903.0005</a>). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation likely occurred de novo in the mother. Studies of patient skeletal muscle tissue showed evidence of a mitochondrial myopathy, including excess lipid droplets, mtDNA deletions, and decreased activities of complexes II-III and IV. Expression of the orthologous mutation in mice resulted in similar clinical and pathologic findings, with evidence of mitochondrial stress and activation of OMA1 (<a href="/entry/617081">617081</a>)-induced mitochondrial fragmentation upon activation of the integrated stress response outside the mitochondria (see ANIMAL MODEL). In addition to a severe myopathy, all 3 patients in this family developed fatal cardiomyopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35700042" 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="#11" class="mim-tip-reference" title="Shammas, M. K., Huang, X., Wu, B. P., Fessler, E., Song, I. Y., Randolph, N. P., Li, Y., Bleck, C. K., Springer, D. A., Fratter, C., Barbosa, I. A., Powers, A. F., Quiros, P. M., Lopez-Otin, C., Jae, L. T., Poulton, J., Narendra, D. P. <strong>OMA1 mediates local and global stress responses against protein misfolding in CHCHD10 mitochondrial myopathy.</strong> J. Clin. Invest. 132: e157504, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35700042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35700042</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35700042[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/10.1172/JCI157504" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35700042">Shammas et al. (2022)</a> generated a mouse model with a heterozygous mutation in the Chchd10 gene that was orthologous to the human G58R mutation (<a href="#0005">615903.0005</a>). Expression of the mutant mouse protein in human cells induced OMA1 activation and caused mitochondrial fragmentation. Heterozygous mutant mice were smaller, had decreased body weight, and died prematurely compared to controls. Mutant mice also showed myopathy with small leg muscles and small muscle fiber size compared to controls, as well as functional motor deficits and decreased cardiac function with atrioventricular heart block. Histologic examination of skeletal muscle showed increased lipid droplets, and both skeletal and cardiac muscle had decreased activities of mitochondrial respiratory complexes I and IV. Cardiac muscle also contained multiple mtDNA deletions and decreased mtDNA copy numbers, suggesting a defect in mtDNA maintenance. The mutant G58R Chchd10 protein formed punctate aggregates within mitochondria in heart and skeletal muscle; mitochondria also contained intracristal inclusions that reflected stress of the inner membrane. There was destabilization of OXPHOS subunits and impaired bioenergetics. These findings were associated with activation of OMA1 (<a href="/entry/617081">617081</a>) in both mouse tissue and skeletal muscle tissue of the human proband carrying the mutation. The G58R mutation in Oma1-null mice was neonatally lethal, suggesting that activation of Oma1 is critical for early survival. Further studies indicated that in the presence of the G58R mutation, OMA1 activated the integrated stress response (ISR) through cleavage of DELE1 (<a href="/entry/615741">615741</a>). The findings were consistent with a toxic gain-of-function effect of the G58R mutation. Of note, mutant mice carrying the S59L mutation (<a href="#0001">615903.0001</a>) had a less severe phenotype, and the mutant S59L protein formed filamentous cellular aggregates that appeared to be outside the mitochondria, suggesting that G58R and S59L have different pathogenetic mechanisms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35700042" 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="Xiao, Y., Zhang, J., Shu, X., Bai, L., Xu, W., Wang, A., Chen, A., Tu, W. Y., Wang, J., Zhang, K., Luo, B., Shen, C. <strong>Loss of mitochondrial protein CHCHD10 in skeletal muscle causes neuromuscular junction impairment.</strong> Hum. Molec. Genet. 29: 1784-1796, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31261376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31261376</a>] [<a href="https://doi.org/10.1093/hmg/ddz154" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31261376">Xiao et al. (2020)</a> found that mice homozygous for conditional deletion of Chchd10 in skeletal muscle were born at the expected mendelian ratio and were viable. However, mutant mice displayed motor defects and neurotransmission impairment, as Chchd10 was required for neurotransmission between motoneuron and skeletal muscle fibers and for NMJ structural integrity. In vitro analysis with C2C12 cells revealed that muscle Chchd10 was required for agrin (AGRN; <a href="/entry/103320">103320</a>)-induced acetylcholine receptor (AChR; see <a href="/entry/100725">100725</a>) clustering. Further analysis showed that muscle Chchd10 was required for mitochondria structure and ATP production. ATP promoted AChR expression in C2C12 cells in vitro and rescued NMJ defects in mice homozygous for Chchd10 deletion in skeletal muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31261376" 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 8 affected members of a large French family with autosomal dominant frontotemporal dementia and/or amyotrophic lateral sclerosis-2 (FTDALS2; <a href="/entry/615911">615911</a>), <a href="#2" class="mim-tip-reference" title="Bannwarth, S., Ait-El-Mkadem, S., Chaussenot, A., Genin, E. C., Lacas-Gervais, S., Fragaki, K., Berg-Alonso, L., Kageyama, Y., Serre, V., Moore, D. G., Verschueren, A., Rouzier, C., and 11 others. <strong>A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement.</strong> Brain 137: 2329-2345, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24934289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24934289</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24934289[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/brain/awu138" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24934289">Bannwarth et al. (2014)</a> identified a heterozygous c.176C-T transition in exon 2 of the CHCHD10 gene, resulting in a ser59-to-leu (S59L) substitution at a highly conserved residue in the hydrophobic N-terminal alpha-helix. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family and was not present in the dbSNP (build 132), Exome Variant Server, or 1000 Genomes Project database, in in-house control exomes, or in 200 matched control alleles. An unrelated Spanish patient with a similar disorder carried the same mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24934289" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Project MinE ALS Sequencing Consortium. <strong>CHCHD10 variants in amyotrophic lateral sclerosis: Where is the evidence?</strong> Ann. Neurol. 84: 110-116, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30014597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30014597</a>] [<a href="https://doi.org/10.1002/ana.25273" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30014597">Project MinE ALS Sequencing Consortium (2018)</a> did not identify the S59L variant in 4,365 ALS patients and 1,832 controls from 7 different countries who underwent sequencing of the CHCHD10 gene, suggesting that it is a rare cause of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30014597" 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>This variant is classified as a variant of unknown significance because its contribution to amyotrophic lateral sclerosis (ALS; see <a href="/entry/105400">105400</a>) has not been confirmed.</p><p>In 4 affected individuals from 2 unrelated German families with ALS, <a href="#7" class="mim-tip-reference" title="Muller, K., Andersen, P. M., Hubers, A., Marroquin, N., Volk, A. E., Danzer, K. M., Meitinger, T., Ludolph, A. C., Strom, T. M., Weishaupt, J. H. <strong>Two novel mutations in conserved codons indicate that CHCHD10 is a gene associated with motor neuron disease. (Letter)</strong> Brain 137: e309, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25113787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25113787</a>] [<a href="https://doi.org/10.1093/brain/awu227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25113787">Muller et al. (2014)</a> identified a heterozygous c.44C-A transversion in the CHCHD10 gene, resulting in an arg15-to-leu (R15L) substitution at a highly conserved residue in a potential N-terminal mitochondrial targeting sequence. The mutation, which was found by whole-exome sequencing of 128 probands with ALS, was not present in the 1000 Genomes Project or Exome Variant Server database, or in 1,000 control exomes. All 4 affected individuals carried the mutation, but at least 4 unaffected mutation-carriers in 1 of the families also carried the mutation, suggesting incomplete penetrance. None of the patients presented with cerebellar deficits or frontotemporo-lobar degeneration. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25113787" 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>Simultaneously and independently, <a href="#5" class="mim-tip-reference" title="Johnson, J. O., Glynn, S. M., Gibbs, J. R., Nalls, M. A., Sabatelli, M., Restagno, G., Drory, V. E., Chio, A., Rogaeva, E., Traynor, B. J. <strong>Mutations in the CHCHD10 gene are a common cause of familial amyotrophic lateral sclerosis. (Letter)</strong> Brain 137: e311, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25261972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25261972</a>] [<a href="https://doi.org/10.1093/brain/awu265" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25261972">Johnson et al. (2014)</a> identified a heterozygous R15L mutation in exon 2 of the CHCHD10 gene in 4 affected members of a family with ALS. The variant was not present in the dbSNP or Exome Sequencing Project database. Direct sequencing of the CHCHD10 gene in 84 probands with familial ALS identified the R15L mutation in 2 additional cases. All patients with the R15L variant shared the same haplotype. Functional studies of the variant were not performed, and further clinical details were not provided. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25261972" 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="#13" class="mim-tip-reference" title="van Rheenen, W., Diekstra, F. P., van den Berg, L. H., Veldink, J. H. <strong>Are CHCHD10 mutations indeed associated with familial amyotrophic lateral sclerosis?</strong> Brain 137: e313, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25348631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25348631</a>] [<a href="https://doi.org/10.1093/brain/awu299" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25348631">Van Rheenen et al. (2014)</a> questioned the strength of the genetic evidence that the R15L variant identified by <a href="#7" class="mim-tip-reference" title="Muller, K., Andersen, P. M., Hubers, A., Marroquin, N., Volk, A. E., Danzer, K. M., Meitinger, T., Ludolph, A. C., Strom, T. M., Weishaupt, J. H. <strong>Two novel mutations in conserved codons indicate that CHCHD10 is a gene associated with motor neuron disease. (Letter)</strong> Brain 137: e309, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25113787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25113787</a>] [<a href="https://doi.org/10.1093/brain/awu227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25113787">Muller et al. (2014)</a> is pathogenic, noting the high number of unaffected carriers in the 2 families. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25113787+25348631" 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 vitro studies by <a href="#1" class="mim-tip-reference" title="Ajroud-Driss, S., Fecto, F., Ajroud, K., Lalani, I., Calvo, S. E., Mootha, V. K., Deng, H.-X., Siddique, N., Tahmoush, A. J., Heiman-Patterson, T. D., Siddique, T. <strong>Mutation in the novel nuclear-encoded mitochondrial protein CHCHD10 in a family with autosomal dominant mitochondrial myopathy.</strong> Neurogenetics 16: 1-9, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25193783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25193783</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25193783[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/10.1007/s10048-014-0421-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25193783">Ajroud-Driss et al. (2015)</a> showed that cells transfected with a variant at the same codon (R15S; <a href="#0004">615903.0004</a>) had normal mitochondrial localization of CHCHD10. These cells were similar to wildtype in that the R15S variant did not cause abnormal fragmentation of mitochondria, suggesting that this mutation is not pathogenic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25193783" 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>Among 4,365 ALS patients and 1,832 controls from 7 different countries who underwent sequencing of the CHCHD10 gene, <a href="#9" class="mim-tip-reference" title="Project MinE ALS Sequencing Consortium. <strong>CHCHD10 variants in amyotrophic lateral sclerosis: Where is the evidence?</strong> Ann. Neurol. 84: 110-116, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30014597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30014597</a>] [<a href="https://doi.org/10.1002/ana.25273" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30014597">Project MinE ALS Sequencing Consortium (2018)</a> found 3 unrelated patients who carried a heterozygous R15L variant. One of these patients had been reported by <a href="#5" class="mim-tip-reference" title="Johnson, J. O., Glynn, S. M., Gibbs, J. R., Nalls, M. A., Sabatelli, M., Restagno, G., Drory, V. E., Chio, A., Rogaeva, E., Traynor, B. J. <strong>Mutations in the CHCHD10 gene are a common cause of familial amyotrophic lateral sclerosis. (Letter)</strong> Brain 137: e311, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25261972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25261972</a>] [<a href="https://doi.org/10.1093/brain/awu265" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25261972">Johnson et al. (2014)</a>. Two had a family history and the other did not. Moreover, the phenotype in some of these patients was atypical for ALS and included myopathic features and deafness. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25261972+30014597" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By RNA sequencing analysis, <a href="#12" class="mim-tip-reference" title="Straub, I. R., Weraarpachai, W., Shoubridge, E. A. <strong>Multi-OMICS study of a CHCHD10 variant causing ALS demonstrates metabolic rewiring and activation of endoplasmic reticulum and mitochondrial unfolded protein responses.</strong> Hum. Molec. Genet. 30: 687-705, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33749723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33749723</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33749723[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/ddab078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33749723">Straub et al. (2021)</a> found that 1-carbon metabolism was reorganized in fibroblasts from ALS patients carrying the CHCHD10 R15L variant compared with 'rescued' patient cells expressing wildtype CHCHD10. Metabolomic analysis revealed a high NADH/NAD+ ratio that caused redox imbalance and stalled the TCA cycle in patient cells. The amount of NADH produced in patient cells could not be used by the respiratory chain to generate ATP due to complex I deficiency resulting from downregulation of several complex I subunits. Furthermore, expression of several transporters responsible for providing substrates for glycolysis and the TCA cycle was altered, leading to accumulation of entry-level substrates of the TCA cycle, like pyruvate and aspartate, outside of mitochondria in the cytosol. This global remodeling of mitochondrial and cellular metabolic pathways in patient cells resulted in activation of an unfolded protein (UPR) stress response mediated by the IRE1 (ERN1; <a href="/entry/604033">604033</a>)/XBP1 (<a href="/entry/194355">194355</a>) pathway in the ER, and by ATF4 (<a href="/entry/604064">604064</a>) and ATF5 (<a href="/entry/606398">606398</a>) in mitochondria, under energetic stress conditions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33749723" 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> rs730880031 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs730880031;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/rs730880031?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=rs730880031" 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=rs730880031" 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=RCV000157070 OR RCV001731148 OR RCV004696857" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000157070, RCV001731148, RCV004696857" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000157070...</a>
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<p>In 55 patients from 17 Finnish families with the Jokela type of spinal muscular atrophy (SMAJ; <a href="/entry/615048">615048</a>), including the original families reported by <a href="#6" class="mim-tip-reference" title="Jokela, M., Penttila, S., Huovinen, S., Hackman, P., Maija Saukkonen, A., Toivanen, J., Udd, B. <strong>Late-onset lower motor neuronopathy: a new autosomal dominant disorder.</strong> Neurology 77: 334-340, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21715705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21715705</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3182267b71" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21715705">Jokela et al. (2011)</a> and a Finnish patient reported by <a href="#7" class="mim-tip-reference" title="Muller, K., Andersen, P. M., Hubers, A., Marroquin, N., Volk, A. E., Danzer, K. M., Meitinger, T., Ludolph, A. C., Strom, T. M., Weishaupt, J. H. <strong>Two novel mutations in conserved codons indicate that CHCHD10 is a gene associated with motor neuron disease. (Letter)</strong> Brain 137: e309, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25113787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25113787</a>] [<a href="https://doi.org/10.1093/brain/awu227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25113787">Muller et al. (2014)</a>, <a href="#8" class="mim-tip-reference" title="Penttila, S., Jokela, M., Bouquin, H., Saukkonen, A. M., Toivanen, J., Udd, B. <strong>Late onset spinal motor neuronopathy is caused by mutation in CHCHD10.</strong> Ann. Neurol. 77: 163-172, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25428574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25428574</a>] [<a href="https://doi.org/10.1002/ana.24319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25428574">Penttila et al. (2015)</a> identified a heterozygous c.197G-T transversion in exon 2 of the CHCHD10 gene, resulting in a gly66-to-val (G66V) substitution at a conserved residue in a highly hydrophobic helix domain. Linkage and haplotype analysis indicated a founder effect. The mutation, which was found by whole-genome sequencing, was not present in the Exome Variant Server or 1000 Genomes Project database, or in 104 Finnish control samples. It segregated completely with the disorder in the families; no unaffected family members carried the mutation. Functional studies of the variant were not performed. <a href="#7" class="mim-tip-reference" title="Muller, K., Andersen, P. M., Hubers, A., Marroquin, N., Volk, A. E., Danzer, K. M., Meitinger, T., Ludolph, A. C., Strom, T. M., Weishaupt, J. H. <strong>Two novel mutations in conserved codons indicate that CHCHD10 is a gene associated with motor neuron disease. (Letter)</strong> Brain 137: e309, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25113787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25113787</a>] [<a href="https://doi.org/10.1093/brain/awu227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25113787">Muller et al. (2014)</a> had previously identified a heterozygous G66V mutation in a Finnish man who was initially diagnosed with a motor neuron disease, but segregation analysis was not available at that time. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21715705+25428574+25113787" 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">rs730880032 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs730880032;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=rs730880032" 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=rs730880032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs730880033 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs730880033;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=rs730880033" 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=rs730880033" 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=RCV000157071 OR RCV002285151" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000157071, RCV002285151" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000157071...</a>
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<p>In all affected individuals in a 5-generation family of Puerto Rican descent with autosomal dominant isolated mitochondrial myopathy (IMMD; <a href="/entry/616209">616209</a>) originally reported by <a href="#4" class="mim-tip-reference" title="Heiman-Patterson, T. D., Argov, Z., Chavin, J. M., Kalman, B., Alder, H., DiMauro, S., Bank, W., Tahmoush, A. J. <strong>Biochemical and genetic studies in a family with mitochondrial myopathy.</strong> Muscle Nerve 20: 1219-1224, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9324076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9324076</a>] [<a href="https://doi.org/10.1002/(sici)1097-4598(199710)20:10<1219::aid-mus2>3.0.co;2-f" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9324076">Heiman-Patterson et al. (1997)</a>, <a href="#1" class="mim-tip-reference" title="Ajroud-Driss, S., Fecto, F., Ajroud, K., Lalani, I., Calvo, S. E., Mootha, V. K., Deng, H.-X., Siddique, N., Tahmoush, A. J., Heiman-Patterson, T. D., Siddique, T. <strong>Mutation in the novel nuclear-encoded mitochondrial protein CHCHD10 in a family with autosomal dominant mitochondrial myopathy.</strong> Neurogenetics 16: 1-9, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25193783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25193783</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25193783[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/10.1007/s10048-014-0421-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25193783">Ajroud-Driss et al. (2015)</a> identified a heterozygous double-missense mutation in cis in the CHCHD10 gene: a c.43C-A transversion, resulting in an arg15-to-ser (R15S) substitution in the potential mitochondrial targeting domain, and a c.172G-C transversion, resulting in a gly58-to-arg (G58R) substitution at a highly conserved residue. The mutation, which was found by linkage analysis and candidate gene sequencing, segregated with the disorder in the family. It was not present in the dbSNP, 1000 Genome Project, or Exome Variant Server database, or in 1,561 Puerto Rican or Hispanic controls. In vitro studies showed that mitochondrial localization of the variant protein was similar to control. Cells transfected with the G58R mutation or the R15S/G58R mutants showed fragmentation of the mitochondria compared to wildtype or cells transfected only with R15S. The findings suggested that the R15S variant may not be pathogenic. <a href="#1" class="mim-tip-reference" title="Ajroud-Driss, S., Fecto, F., Ajroud, K., Lalani, I., Calvo, S. E., Mootha, V. K., Deng, H.-X., Siddique, N., Tahmoush, A. J., Heiman-Patterson, T. D., Siddique, T. <strong>Mutation in the novel nuclear-encoded mitochondrial protein CHCHD10 in a family with autosomal dominant mitochondrial myopathy.</strong> Neurogenetics 16: 1-9, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25193783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25193783</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25193783[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/10.1007/s10048-014-0421-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25193783">Ajroud-Driss et al. (2015)</a> noted that the G58R variant occurs adjacent to another mutation (S59L; <a href="#0001">615903.0001</a>) identified in a large family with a different neurologic disease, FTDALS2 (<a href="/entry/615911">615911</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25193783+9324076" 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="Shammas, M. K., Huang, X., Wu, B. P., Fessler, E., Song, I. Y., Randolph, N. P., Li, Y., Bleck, C. K., Springer, D. A., Fratter, C., Barbosa, I. A., Powers, A. F., Quiros, P. M., Lopez-Otin, C., Jae, L. T., Poulton, J., Narendra, D. P. <strong>OMA1 mediates local and global stress responses against protein misfolding in CHCHD10 mitochondrial myopathy.</strong> J. Clin. Invest. 132: e157504, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35700042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35700042</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35700042[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/10.1172/JCI157504" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35700042">Shammas et al. (2022)</a> identified a heterozygous G58R mutation (<a href="#0005">615903.0005</a>) in the CHCHD10 gene in 3 affected members of a family from the UK with IMMD with fatal cardiomyopathy. The authors stated that the G58R mutation in these individuals was found 'in isolation,' i.e., without the R15S variant. <a href="#11" class="mim-tip-reference" title="Shammas, M. K., Huang, X., Wu, B. P., Fessler, E., Song, I. Y., Randolph, N. P., Li, Y., Bleck, C. K., Springer, D. A., Fratter, C., Barbosa, I. A., Powers, A. F., Quiros, P. M., Lopez-Otin, C., Jae, L. T., Poulton, J., Narendra, D. P. <strong>OMA1 mediates local and global stress responses against protein misfolding in CHCHD10 mitochondrial myopathy.</strong> J. Clin. Invest. 132: e157504, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35700042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35700042</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35700042[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/10.1172/JCI157504" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35700042">Shammas et al. (2022)</a> noted that the phenotype in their family was more severe than that in the family reported by <a href="#1" class="mim-tip-reference" title="Ajroud-Driss, S., Fecto, F., Ajroud, K., Lalani, I., Calvo, S. E., Mootha, V. K., Deng, H.-X., Siddique, N., Tahmoush, A. J., Heiman-Patterson, T. D., Siddique, T. <strong>Mutation in the novel nuclear-encoded mitochondrial protein CHCHD10 in a family with autosomal dominant mitochondrial myopathy.</strong> Neurogenetics 16: 1-9, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25193783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25193783</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25193783[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/10.1007/s10048-014-0421-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25193783">Ajroud-Driss et al. (2015)</a>, raising the possibility that the R15S variant may offer a protective effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=35700042+25193783" 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 MYOPATHY, ISOLATED MITOCHONDRIAL, AUTOSOMAL DOMINANT</strong>
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CHCHD10, GLY58ARG
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000157071 OR RCV002285151" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000157071, RCV002285151" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000157071...</a>
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<p>In a mother and her 2 sons (family UK) with autosomal dominant isolated mitochondrial myopathy (IMMD; <a href="/entry/616209">616209</a>), <a href="#11" class="mim-tip-reference" title="Shammas, M. K., Huang, X., Wu, B. P., Fessler, E., Song, I. Y., Randolph, N. P., Li, Y., Bleck, C. K., Springer, D. A., Fratter, C., Barbosa, I. A., Powers, A. F., Quiros, P. M., Lopez-Otin, C., Jae, L. T., Poulton, J., Narendra, D. P. <strong>OMA1 mediates local and global stress responses against protein misfolding in CHCHD10 mitochondrial myopathy.</strong> J. Clin. Invest. 132: e157504, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35700042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35700042</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35700042[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/10.1172/JCI157504" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35700042">Shammas et al. (2022)</a> identified a heterozygous gly58-to-arg (G58R) substitution in the CHCHD10 gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation likely occurred de novo in the mother. Studies of patient skeletal muscle tissue showed evidence of a mitochondrial myopathy, including excess lipid droplets, mtDNA deletions, and decreased activities of complexes II-III and IV. Expression of the orthologous mutation in mice resulted in similar clinical and pathologic findings, with evidence of mitochondrial stress and activation of OMA1 (<a href="/entry/617081">617081</a>) that induced mitochondrial fragmentation and activated the integrated stress response outside the mitochondria (see ANIMAL MODEL). In addition to a severe myopathy, all 3 patients in this family developed fatal cardiomyopathy. The mother in the family had originally been reported as a child by <a href="#10" class="mim-tip-reference" title="Salmon, M. A., Esiri, M. M., Ruderman, N. B. <strong>Myopathic disorder associated with mitochondrial abnormalities, hyperglycaemia, and hyperketonaemia.</strong> Lancet 2: 290-2, 1971.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4104978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4104978</a>] [<a href="https://doi.org/10.1016/s0140-6736(71)91335-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4104978">Salmon et al. (1971)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=35700042+4104978" 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>REFERENCES</strong>
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<a id="Ajroud-Driss2015" class="mim-anchor"></a>
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Ajroud-Driss, S., Fecto, F., Ajroud, K., Lalani, I., Calvo, S. E., Mootha, V. K., Deng, H.-X., Siddique, N., Tahmoush, A. J., Heiman-Patterson, T. D., Siddique, T.
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<strong>Mutation in the novel nuclear-encoded mitochondrial protein CHCHD10 in a family with autosomal dominant mitochondrial myopathy.</strong>
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Neurogenetics 16: 1-9, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25193783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25193783</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25193783[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=25193783" 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/s10048-014-0421-1" target="_blank">Full Text</a>]
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Bannwarth, S., Ait-El-Mkadem, S., Chaussenot, A., Genin, E. C., Lacas-Gervais, S., Fragaki, K., Berg-Alonso, L., Kageyama, Y., Serre, V., Moore, D. G., Verschueren, A., Rouzier, C., and 11 others.
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<strong>A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement.</strong>
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Brain 137: 2329-2345, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24934289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24934289</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24934289[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=24934289" 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/brain/awu138" target="_blank">Full Text</a>]
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Hartz, P. A.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 7/24/2014.
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Heiman-Patterson, T. D., Argov, Z., Chavin, J. M., Kalman, B., Alder, H., DiMauro, S., Bank, W., Tahmoush, A. J.
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<strong>Biochemical and genetic studies in a family with mitochondrial myopathy.</strong>
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Muscle Nerve 20: 1219-1224, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9324076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9324076</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9324076" 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/(sici)1097-4598(199710)20:10<1219::aid-mus2>3.0.co;2-f" target="_blank">Full Text</a>]
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Johnson, J. O., Glynn, S. M., Gibbs, J. R., Nalls, M. A., Sabatelli, M., Restagno, G., Drory, V. E., Chio, A., Rogaeva, E., Traynor, B. J.
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<strong>Mutations in the CHCHD10 gene are a common cause of familial amyotrophic lateral sclerosis. (Letter)</strong>
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Brain 137: e311, 2014. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25261972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25261972</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25261972" 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/brain/awu265" target="_blank">Full Text</a>]
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Jokela, M., Penttila, S., Huovinen, S., Hackman, P., Maija Saukkonen, A., Toivanen, J., Udd, B.
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<strong>Late-onset lower motor neuronopathy: a new autosomal dominant disorder.</strong>
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Neurology 77: 334-340, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21715705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21715705</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21715705" 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/10.1212/WNL.0b013e3182267b71" target="_blank">Full Text</a>]
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Muller, K., Andersen, P. M., Hubers, A., Marroquin, N., Volk, A. E., Danzer, K. M., Meitinger, T., Ludolph, A. C., Strom, T. M., Weishaupt, J. H.
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<strong>Two novel mutations in conserved codons indicate that CHCHD10 is a gene associated with motor neuron disease. (Letter)</strong>
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Brain 137: e309, 2014. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25113787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25113787</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25113787" 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/brain/awu227" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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|
<a id="8" class="mim-anchor"></a>
|
|
<a id="Penttila2015" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Penttila, S., Jokela, M., Bouquin, H., Saukkonen, A. M., Toivanen, J., Udd, B.
|
|
<strong>Late onset spinal motor neuronopathy is caused by mutation in CHCHD10.</strong>
|
|
Ann. Neurol. 77: 163-172, 2015.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25428574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25428574</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25428574" 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.24319" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="9" class="mim-anchor"></a>
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<a id="{Project MinE ALS Sequencing Consortium}2018" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Project MinE ALS Sequencing Consortium.
|
|
<strong>CHCHD10 variants in amyotrophic lateral sclerosis: Where is the evidence?</strong>
|
|
Ann. Neurol. 84: 110-116, 2018.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30014597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30014597</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30014597" 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.25273" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="10" class="mim-anchor"></a>
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<a id="Salmon1971" class="mim-anchor"></a>
|
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<div class="">
|
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<p class="mim-text-font">
|
|
Salmon, M. A., Esiri, M. M., Ruderman, N. B.
|
|
<strong>Myopathic disorder associated with mitochondrial abnormalities, hyperglycaemia, and hyperketonaemia.</strong>
|
|
Lancet 2: 290-2, 1971.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4104978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4104978</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4104978" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(71)91335-3" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="11" class="mim-anchor"></a>
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<a id="Shammas2022" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Shammas, M. K., Huang, X., Wu, B. P., Fessler, E., Song, I. Y., Randolph, N. P., Li, Y., Bleck, C. K., Springer, D. A., Fratter, C., Barbosa, I. A., Powers, A. F., Quiros, P. M., Lopez-Otin, C., Jae, L. T., Poulton, J., Narendra, D. P.
|
|
<strong>OMA1 mediates local and global stress responses against protein misfolding in CHCHD10 mitochondrial myopathy.</strong>
|
|
J. Clin. Invest. 132: e157504, 2022.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35700042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35700042</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35700042[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=35700042" 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/10.1172/JCI157504" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Straub2021" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Straub, I. R., Weraarpachai, W., Shoubridge, E. A.
|
|
<strong>Multi-OMICS study of a CHCHD10 variant causing ALS demonstrates metabolic rewiring and activation of endoplasmic reticulum and mitochondrial unfolded protein responses.</strong>
|
|
Hum. Molec. Genet. 30: 687-705, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33749723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33749723</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33749723[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=33749723" 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/ddab078" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="van Rheenen2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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van Rheenen, W., Diekstra, F. P., van den Berg, L. H., Veldink, J. H.
|
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<strong>Are CHCHD10 mutations indeed associated with familial amyotrophic lateral sclerosis?</strong>
|
|
Brain 137: e313, 2014. Note: Electronic Article.
|
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|
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25348631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25348631</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25348631" 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/brain/awu299" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Xiao2020" class="mim-anchor"></a>
|
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<div class="">
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<p class="mim-text-font">
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Xiao, Y., Zhang, J., Shu, X., Bai, L., Xu, W., Wang, A., Chen, A., Tu, W. Y., Wang, J., Zhang, K., Luo, B., Shen, C.
|
|
<strong>Loss of mitochondrial protein CHCHD10 in skeletal muscle causes neuromuscular junction impairment.</strong>
|
|
Hum. Molec. Genet. 29: 1784-1796, 2020.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31261376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31261376</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31261376" 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/ddz154" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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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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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
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Bao Lige - updated : 10/06/2022
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</span>
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</div>
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</div>
|
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<div class="row collapse" id="mimCollapseContributors">
|
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 08/17/2022<br>Cassandra L. Kniffin - updated : 1/29/2015<br>Cassandra L. Kniffin - updated : 7/29/2014
|
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
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<span class="text-nowrap mim-text-font">
|
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Creation Date:
|
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
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Patricia A. Hartz : 7/24/2014
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
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</span>
|
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 01/29/2024
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</span>
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</div>
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</div>
|
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<div class="row collapse" id="mimCollapseEditHistory">
|
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
|
|
mgross : 10/06/2022<br>alopez : 08/25/2022<br>ckniffin : 08/17/2022<br>alopez : 10/25/2016<br>alopez : 02/02/2015<br>mcolton : 1/30/2015<br>ckniffin : 1/29/2015<br>carol : 7/29/2014<br>mcolton : 7/29/2014<br>ckniffin : 7/29/2014<br>alopez : 7/24/2014<br>alopez : 7/24/2014<br>alopez : 7/24/2014<br>alopez : 7/23/2014
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</span>
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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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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
|
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<span class="mim-font">
|
|
<strong>*</strong> 615903
|
|
</span>
|
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</h3>
|
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</div>
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<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
COILED-COIL-HELIX-COILED-COIL-HELIX DOMAIN-CONTAINING PROTEIN 10; CHCHD10
|
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|
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</span>
|
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</h3>
|
|
</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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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: CHCHD10</em></strong>
|
|
</span>
|
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</p>
|
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</div>
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<div>
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<p>
|
|
<span class="mim-text-font">
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|
|
<strong>SNOMEDCT:</strong> 1222644009;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
|
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<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: 22q11.23
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 22:23,765,834-23,767,972 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
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<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="3">
|
|
<span class="mim-font">
|
|
22q11.23
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
?Myopathy, isolated mitochondrial, autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
616209
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
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|
|
</tr>
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|
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|
|
|
|
|
|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Frontotemporal dementia and/or amyotrophic lateral sclerosis 2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
615911
|
|
</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">
|
|
Spinal muscular atrophy, Jokela type
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
615048
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
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<div>
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|
<br />
|
|
</div>
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<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
|
<span class="mim-text-font">
|
|
<p>CHCHD10 is a relatively small protein of the mitochondrial intermembrane space that is enriched at cristae junctions. It is predicted to be involved in oxidative phosphorylation or in maintenance of cristae morphology (Bannwarth et al., 2014). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<span class="mim-text-font">
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<p>By whole-exome sequencing, Bannwarth et al. (2014) identified the CHCHD10 gene. The deduced protein has a nonstructured N-terminal region, followed by a highly hydrophobic helix and a C-terminal CHCH domain characterized by a Cx(9)C motif and 2 additional cysteines; the 4 cysteine residues together are predicted to form 2 disulfide bonds. Western blot analysis of 9 human tissues detected ubiquitous CHCHD10 expression, with highest expression in heart and liver and lowest expression in spleen. Immunohistochemical and immunogold electron microscopy of HeLa cells localized CHCHD10 to mitochondria, where it was enriched at cristae junctions. Protease treatment and differential extraction of HeLa cell mitochondria revealed that CHCHD10 is a soluble protein of the intermembrane space. </p><p>Ajroud-Driss et al. (2015) found that the CHCHD10 gene is highly expressed in human skeletal muscle. </p><p>By immunoblot analysis, Xiao et al. (2020) showed that Chchd10 was highly expressed in mouse skeletal muscle, whereas expression was low in spinal cord and sciatic nerve. In skeletal muscle, Chchd10 expression gradually increased after birth and peaked after 2 weeks. Further analysis revealed that Chchd10 expression was enriched at the postsynapse of mouse neuromuscular junction (NMJ), a tripartite synapse consisting of muscle fibers, Schwann cells, and motoneuron terminals. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Ajroud-Driss et al. (2015) reported that the CHCHD10 gene contains 4 exons. </p>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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<span class="mim-text-font">
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<p>Hartz (2014) mapped the CHCHD10 gene to chromosome 22q11.23 based on an alignment of the CHCHD10 sequence (GenBank BC065232) with the genomic sequence (GRCh37).</p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p><strong><em>Frontotemporal Dementia and/or Amyotrophic Lateral Sclerosis-2, Autosomal Dominant</em></strong></p><p>
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In 8 affected members of a large French family with autosomal dominant frontotemporal dementia and/or amyotrophic lateral sclerosis-2 (FTDALS2; 615911), Bannwarth et al. (2014) identified a heterozygous missense mutation in the CHCHD10 gene (S59L; 615903.0001). The mutation was found by whole-exome sequencing and segregated with the disorder in the family. Screening of the CHCHD10 gene in 21 additional families with a similar disorder identified the same heterozygous mutation in 1 proband of Spanish descent. Overexpression of the mutant protein in HeLa cells led to fragmentation of the mitochondrial network as well as major ultrastructural abnormalities, similar to those observed in patient cells. The findings implicated a role for dysfunctional mitochondria in the pathogenesis of late-onset frontotemporal dementia with motor neuron disease. </p><p>Among 4,365 ALS patients and 1,832 controls from 7 different countries who underwent sequencing of the CHCHD10 gene, Project MinE ALS Sequencing Consortium (2018) found no significantly increased disease-associated mutation burden, suggesting that mutations in the CHCHD10 gene are rare in typical ALS. Three ALS-specific variants were identified in 5 unrelated patients. One woman with ALS without dementia and no family history of the disease carried a heterozygous R11G variant. Three additional unrelated patients, 1 Dutch and 2 American, carried a heterozygous R15L variant (615903.0002); 2 had a positive family history whereas the other did not. One of these patients had been reported by Johnson et al. (2014). Finally, a Belgian patient carried a heterozygous P80L variant. The phenotype in some of these patients was atypical for ALS and included myopathic features and deafness. S59L was not found in either patients or controls. Functional studies of the variants and studies of patient cells were not performed. </p><p><strong><em>Spinal Muscular Atrophy, Jokela Type</em></strong></p><p>
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In 55 patients from 17 Finnish families with the Jokela type of spinal muscular atrophy (SMAJ; 615048), including the original families reported by Jokela et al. (2011) and a Finnish patient reported by Muller et al. (2014), Penttila et al. (2015) identified the same heterozygous missense mutation in the CHCHD10 gene (G66V; 615903.0003). The mutation, which was found by linkage analysis and whole-genome sequencing, segregated with the disorder in all families. Haplotype analysis indicated a founder effect. Functional studies of the variant were not performed. </p><p><strong><em>Mitochondrial Myopathy, Isolated, Autosomal Dominant</em></strong></p><p>
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In all affected individuals in a 5-generation family of Puerto Rican descent with autosomal dominant isolated mitochondrial myopathy (IMMD; 616209) originally reported by Heiman-Patterson et al. (1997), Ajroud-Driss et al. (2015) identified a heterozygous missense mutation in the CHCHD10 gene (R15S/G58R; 615903.0004). The mutation, which was found by linkage analysis and candidate gene sequencing, segregated with the disorder in the family. In vitro studies showed that mitochondrial localization of the variant protein was similar to control. Cells transfected with the G58R mutation or the R15S/G58R mutants showed fragmentation of the mitochondria compared to wildtype or cells transfected only with R15S. The findings suggested that the R15S variant may not be pathogenic. Ajroud-Driss et al. (2015) noted that the G58R variant is adjacent to a mutation (S59L; 615903.0001) identified in a large family with a different neurologic disease, FTDALS2, and concluded that multiple phenotypes can result from defects in tissues that are highly dependent on oxidative phosphorylation, including muscle and nervous system tissues. </p><p>In a mother and her 2 sons (family UK) with IMMD, Shammas et al. (2022) identified a heterozygous missense mutation in the CHCHD10 gene (G58R; 615903.0005). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation likely occurred de novo in the mother. Studies of patient skeletal muscle tissue showed evidence of a mitochondrial myopathy, including excess lipid droplets, mtDNA deletions, and decreased activities of complexes II-III and IV. Expression of the orthologous mutation in mice resulted in similar clinical and pathologic findings, with evidence of mitochondrial stress and activation of OMA1 (617081)-induced mitochondrial fragmentation upon activation of the integrated stress response outside the mitochondria (see ANIMAL MODEL). In addition to a severe myopathy, all 3 patients in this family developed fatal cardiomyopathy. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Shammas et al. (2022) generated a mouse model with a heterozygous mutation in the Chchd10 gene that was orthologous to the human G58R mutation (615903.0005). Expression of the mutant mouse protein in human cells induced OMA1 activation and caused mitochondrial fragmentation. Heterozygous mutant mice were smaller, had decreased body weight, and died prematurely compared to controls. Mutant mice also showed myopathy with small leg muscles and small muscle fiber size compared to controls, as well as functional motor deficits and decreased cardiac function with atrioventricular heart block. Histologic examination of skeletal muscle showed increased lipid droplets, and both skeletal and cardiac muscle had decreased activities of mitochondrial respiratory complexes I and IV. Cardiac muscle also contained multiple mtDNA deletions and decreased mtDNA copy numbers, suggesting a defect in mtDNA maintenance. The mutant G58R Chchd10 protein formed punctate aggregates within mitochondria in heart and skeletal muscle; mitochondria also contained intracristal inclusions that reflected stress of the inner membrane. There was destabilization of OXPHOS subunits and impaired bioenergetics. These findings were associated with activation of OMA1 (617081) in both mouse tissue and skeletal muscle tissue of the human proband carrying the mutation. The G58R mutation in Oma1-null mice was neonatally lethal, suggesting that activation of Oma1 is critical for early survival. Further studies indicated that in the presence of the G58R mutation, OMA1 activated the integrated stress response (ISR) through cleavage of DELE1 (615741). The findings were consistent with a toxic gain-of-function effect of the G58R mutation. Of note, mutant mice carrying the S59L mutation (615903.0001) had a less severe phenotype, and the mutant S59L protein formed filamentous cellular aggregates that appeared to be outside the mitochondria, suggesting that G58R and S59L have different pathogenetic mechanisms. </p><p>Xiao et al. (2020) found that mice homozygous for conditional deletion of Chchd10 in skeletal muscle were born at the expected mendelian ratio and were viable. However, mutant mice displayed motor defects and neurotransmission impairment, as Chchd10 was required for neurotransmission between motoneuron and skeletal muscle fibers and for NMJ structural integrity. In vitro analysis with C2C12 cells revealed that muscle Chchd10 was required for agrin (AGRN; 103320)-induced acetylcholine receptor (AChR; see 100725) clustering. Further analysis showed that muscle Chchd10 was required for mitochondria structure and ATP production. ATP promoted AChR expression in C2C12 cells in vitro and rescued NMJ defects in mice homozygous for Chchd10 deletion in skeletal muscle. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>5 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS 2</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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CHCHD10, SER59LEU
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<br />
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SNP: rs587777574,
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ClinVar: RCV000128857, RCV000192232, RCV001268565
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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 8 affected members of a large French family with autosomal dominant frontotemporal dementia and/or amyotrophic lateral sclerosis-2 (FTDALS2; 615911), Bannwarth et al. (2014) identified a heterozygous c.176C-T transition in exon 2 of the CHCHD10 gene, resulting in a ser59-to-leu (S59L) substitution at a highly conserved residue in the hydrophobic N-terminal alpha-helix. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family and was not present in the dbSNP (build 132), Exome Variant Server, or 1000 Genomes Project database, in in-house control exomes, or in 200 matched control alleles. An unrelated Spanish patient with a similar disorder carried the same mutation. </p><p>Project MinE ALS Sequencing Consortium (2018) did not identify the S59L variant in 4,365 ALS patients and 1,832 controls from 7 different countries who underwent sequencing of the CHCHD10 gene, suggesting that it is a rare cause of the disorder. </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>.0002 VARIANT OF UNKNOWN SIGNIFICANCE</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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CHCHD10, ARG15LEU
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<br />
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SNP: rs730880030,
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ClinVar: RCV000157069, RCV000804540, RCV001731147, RCV002463652
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>This variant is classified as a variant of unknown significance because its contribution to amyotrophic lateral sclerosis (ALS; see 105400) has not been confirmed.</p><p>In 4 affected individuals from 2 unrelated German families with ALS, Muller et al. (2014) identified a heterozygous c.44C-A transversion in the CHCHD10 gene, resulting in an arg15-to-leu (R15L) substitution at a highly conserved residue in a potential N-terminal mitochondrial targeting sequence. The mutation, which was found by whole-exome sequencing of 128 probands with ALS, was not present in the 1000 Genomes Project or Exome Variant Server database, or in 1,000 control exomes. All 4 affected individuals carried the mutation, but at least 4 unaffected mutation-carriers in 1 of the families also carried the mutation, suggesting incomplete penetrance. None of the patients presented with cerebellar deficits or frontotemporo-lobar degeneration. Functional studies of the variant were not performed. </p><p>Simultaneously and independently, Johnson et al. (2014) identified a heterozygous R15L mutation in exon 2 of the CHCHD10 gene in 4 affected members of a family with ALS. The variant was not present in the dbSNP or Exome Sequencing Project database. Direct sequencing of the CHCHD10 gene in 84 probands with familial ALS identified the R15L mutation in 2 additional cases. All patients with the R15L variant shared the same haplotype. Functional studies of the variant were not performed, and further clinical details were not provided. </p><p>Van Rheenen et al. (2014) questioned the strength of the genetic evidence that the R15L variant identified by Muller et al. (2014) is pathogenic, noting the high number of unaffected carriers in the 2 families. </p><p>In vitro studies by Ajroud-Driss et al. (2015) showed that cells transfected with a variant at the same codon (R15S; 615903.0004) had normal mitochondrial localization of CHCHD10. These cells were similar to wildtype in that the R15S variant did not cause abnormal fragmentation of mitochondria, suggesting that this mutation is not pathogenic. </p><p>Among 4,365 ALS patients and 1,832 controls from 7 different countries who underwent sequencing of the CHCHD10 gene, Project MinE ALS Sequencing Consortium (2018) found 3 unrelated patients who carried a heterozygous R15L variant. One of these patients had been reported by Johnson et al. (2014). Two had a family history and the other did not. Moreover, the phenotype in some of these patients was atypical for ALS and included myopathic features and deafness. Functional studies of the variant and studies of patient cells were not performed. </p><p>By RNA sequencing analysis, Straub et al. (2021) found that 1-carbon metabolism was reorganized in fibroblasts from ALS patients carrying the CHCHD10 R15L variant compared with 'rescued' patient cells expressing wildtype CHCHD10. Metabolomic analysis revealed a high NADH/NAD+ ratio that caused redox imbalance and stalled the TCA cycle in patient cells. The amount of NADH produced in patient cells could not be used by the respiratory chain to generate ATP due to complex I deficiency resulting from downregulation of several complex I subunits. Furthermore, expression of several transporters responsible for providing substrates for glycolysis and the TCA cycle was altered, leading to accumulation of entry-level substrates of the TCA cycle, like pyruvate and aspartate, outside of mitochondria in the cytosol. This global remodeling of mitochondrial and cellular metabolic pathways in patient cells resulted in activation of an unfolded protein (UPR) stress response mediated by the IRE1 (ERN1; 604033)/XBP1 (194355) pathway in the ER, and by ATF4 (604064) and ATF5 (606398) in mitochondria, under energetic stress conditions. </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>.0003 SPINAL MUSCULAR ATROPHY, JOKELA TYPE</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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CHCHD10, GLY66VAL
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<br />
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SNP: rs730880031,
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gnomAD: rs730880031,
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ClinVar: RCV000157070, RCV001731148, RCV004696857
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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 55 patients from 17 Finnish families with the Jokela type of spinal muscular atrophy (SMAJ; 615048), including the original families reported by Jokela et al. (2011) and a Finnish patient reported by Muller et al. (2014), Penttila et al. (2015) identified a heterozygous c.197G-T transversion in exon 2 of the CHCHD10 gene, resulting in a gly66-to-val (G66V) substitution at a conserved residue in a highly hydrophobic helix domain. Linkage and haplotype analysis indicated a founder effect. The mutation, which was found by whole-genome sequencing, was not present in the Exome Variant Server or 1000 Genomes Project database, or in 104 Finnish control samples. It segregated completely with the disorder in the families; no unaffected family members carried the mutation. Functional studies of the variant were not performed. Muller et al. (2014) had previously identified a heterozygous G66V mutation in a Finnish man who was initially diagnosed with a motor neuron disease, but segregation analysis was not available at that time. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 MYOPATHY, ISOLATED MITOCHONDRIAL, AUTOSOMAL DOMINANT</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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CHCHD10, ARG15SER AND GLY58ARG
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<br />
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SNP: rs730880032, rs730880033,
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ClinVar: RCV000157071, RCV002285151
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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 all affected individuals in a 5-generation family of Puerto Rican descent with autosomal dominant isolated mitochondrial myopathy (IMMD; 616209) originally reported by Heiman-Patterson et al. (1997), Ajroud-Driss et al. (2015) identified a heterozygous double-missense mutation in cis in the CHCHD10 gene: a c.43C-A transversion, resulting in an arg15-to-ser (R15S) substitution in the potential mitochondrial targeting domain, and a c.172G-C transversion, resulting in a gly58-to-arg (G58R) substitution at a highly conserved residue. The mutation, which was found by linkage analysis and candidate gene sequencing, segregated with the disorder in the family. It was not present in the dbSNP, 1000 Genome Project, or Exome Variant Server database, or in 1,561 Puerto Rican or Hispanic controls. In vitro studies showed that mitochondrial localization of the variant protein was similar to control. Cells transfected with the G58R mutation or the R15S/G58R mutants showed fragmentation of the mitochondria compared to wildtype or cells transfected only with R15S. The findings suggested that the R15S variant may not be pathogenic. Ajroud-Driss et al. (2015) noted that the G58R variant occurs adjacent to another mutation (S59L; 615903.0001) identified in a large family with a different neurologic disease, FTDALS2 (615911). </p><p>Shammas et al. (2022) identified a heterozygous G58R mutation (615903.0005) in the CHCHD10 gene in 3 affected members of a family from the UK with IMMD with fatal cardiomyopathy. The authors stated that the G58R mutation in these individuals was found 'in isolation,' i.e., without the R15S variant. Shammas et al. (2022) noted that the phenotype in their family was more severe than that in the family reported by Ajroud-Driss et al. (2015), raising the possibility that the R15S variant may offer a protective effect. </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 MYOPATHY, ISOLATED MITOCHONDRIAL, AUTOSOMAL DOMINANT</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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CHCHD10, GLY58ARG
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<br />
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ClinVar: RCV000157071, RCV002285151
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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 mother and her 2 sons (family UK) with autosomal dominant isolated mitochondrial myopathy (IMMD; 616209), Shammas et al. (2022) identified a heterozygous gly58-to-arg (G58R) substitution in the CHCHD10 gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation likely occurred de novo in the mother. Studies of patient skeletal muscle tissue showed evidence of a mitochondrial myopathy, including excess lipid droplets, mtDNA deletions, and decreased activities of complexes II-III and IV. Expression of the orthologous mutation in mice resulted in similar clinical and pathologic findings, with evidence of mitochondrial stress and activation of OMA1 (617081) that induced mitochondrial fragmentation and activated the integrated stress response outside the mitochondria (see ANIMAL MODEL). In addition to a severe myopathy, all 3 patients in this family developed fatal cardiomyopathy. The mother in the family had originally been reported as a child by Salmon et al. (1971). </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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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Ajroud-Driss, S., Fecto, F., Ajroud, K., Lalani, I., Calvo, S. E., Mootha, V. K., Deng, H.-X., Siddique, N., Tahmoush, A. J., Heiman-Patterson, T. D., Siddique, T.
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<strong>Mutation in the novel nuclear-encoded mitochondrial protein CHCHD10 in a family with autosomal dominant mitochondrial myopathy.</strong>
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Neurogenetics 16: 1-9, 2015.
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[PubMed: 25193783]
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[Full Text: https://doi.org/10.1007/s10048-014-0421-1]
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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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Bannwarth, S., Ait-El-Mkadem, S., Chaussenot, A., Genin, E. C., Lacas-Gervais, S., Fragaki, K., Berg-Alonso, L., Kageyama, Y., Serre, V., Moore, D. G., Verschueren, A., Rouzier, C., and 11 others.
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<strong>A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement.</strong>
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Brain 137: 2329-2345, 2014.
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<strong>Two novel mutations in conserved codons indicate that CHCHD10 is a gene associated with motor neuron disease. (Letter)</strong>
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Penttila, S., Jokela, M., Bouquin, H., Saukkonen, A. M., Toivanen, J., Udd, B.
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Straub, I. R., Weraarpachai, W., Shoubridge, E. A.
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<strong>Multi-OMICS study of a CHCHD10 variant causing ALS demonstrates metabolic rewiring and activation of endoplasmic reticulum and mitochondrial unfolded protein responses.</strong>
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van Rheenen, W., Diekstra, F. P., van den Berg, L. H., Veldink, J. H.
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<strong>Are CHCHD10 mutations indeed associated with familial amyotrophic lateral sclerosis?</strong>
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Xiao, Y., Zhang, J., Shu, X., Bai, L., Xu, W., Wang, A., Chen, A., Tu, W. Y., Wang, J., Zhang, K., Luo, B., Shen, C.
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<strong>Loss of mitochondrial protein CHCHD10 in skeletal muscle causes neuromuscular junction impairment.</strong>
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