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Entry
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- *300056 - HOLOCYTOCHROME C SYNTHASE; HCCS
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*300056</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<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="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/300056">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li 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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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000004961;t=ENST00000380762" 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=3052" 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=300056" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000004961;t=ENST00000380762" 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_001122608,NM_001171991,NM_005333" 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_005333" 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=300056" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=02085&isoform_id=02085_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/HCCS" 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/1209635,1705694,13111709,51476820,63102457,119619189,119619190,119619191,169790849,169790851,193783622,285002259" 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/P53701" 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=3052" 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=ENSG00000004961;t=ENST00000380762" 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=HCCS" 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=HCCS" 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+3052" 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/HCCS" 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:3052" 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/3052" 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=chrX&hgg_gene=ENST00000380762.5&hgg_start=11111332&hgg_end=11123086&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/gene-dosage/HGNC:4837" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/hccs" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=300056[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 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=300056[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/HCCS/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000004961" 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=HCCS" 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=HCCS" 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=HCCS" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.LOVD.nl/HCCS" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=HCCS&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/PA29214" 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:4837" 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/FBgn0038925.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:106911" 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/HCCS#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:106911" 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/3052/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=3052" 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=WBGene00011527;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-000607-78" 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:3052" 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=HCCS&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> 721879006<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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300056
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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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HOLOCYTOCHROME C SYNTHASE; HCCS
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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=HCCS" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">HCCS</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/X/55?start=-3&limit=10&highlight=55">Xp22.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chrX:11111332-11123086&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'})">X:11,111,332-11,123,086</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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</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="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/X/55?start=-3&limit=10&highlight=55">
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Xp22.2
|
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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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Linear skin defects with multiple congenital anomalies 1
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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/309801"> 309801 </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="X-linked dominant">XLD</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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</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">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
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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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<li><a href="/graph/linear/300056" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
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<li><a href="/graph/radial/300056" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</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="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>HCCS is a highly conserved gene from fungi to metazoans that encodes holocytochrome c-type synthase, which is located on the outer surface of the inner mitochondrial membrane. HCCS catalyzes covalent attachment of heme to both cytochrome c (CYTC, or CYCS; <a href="/entry/123970">123970</a>) and cytochrome c1 (CYTC1, or CYC1; <a href="/entry/123980">123980</a>), which are crucial components of the mitochondrial respiratory chain (summary by <a href="#1" class="mim-tip-reference" title="Indrieri, A., Conte, I., Chesi, G., Romano, A., Quartararo, J., Tate, R., Ghezzi, D., Zeviani, M., Goffrini, P., Ferrero, I., Bovolenta, P., Franco, B. <strong>The impairment of HCCS leads to MLS syndrome by activating a non-canonical cell death pathway in the brain and eyes.</strong> EMBO Molec. Med. 5: 280-293, 2013. Note: Erratum: EMBO Molec. Med. 6: 849 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23239471/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23239471</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23239471[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/10.1002/emmm.201201739" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23239471">Indrieri et al., 2013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23239471" 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>Using a cross-species conservation strategy, <a href="#4" class="mim-tip-reference" title="Schaefer, L., Ballabio, A., Zoghbi, H. Y. <strong>Cloning and characterization of a putative human holocytochrome c-type synthetase gene (HCCS) isolated from the critical region for microphthalmia with linear skin defects (MLS).</strong> Genomics 34: 166-172, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8661044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8661044</a>] [<a href="https://doi.org/10.1006/geno.1996.0261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8661044">Schaefer et al. (1996)</a> isolated an expressed sequence from a 450- to 550-kb critical region for a microphthalmia syndrome with linear skin defects (LSDMCA1, MLS; <a href="/entry/309801">309801</a>) on Xp22 by screening a human embryo cDNA library. Northern analysis demonstrated a transcript of approximately 2.6 kb in all tissues examined, with weaker expression of 1.2- and 5.2-kb transcripts. The strongest expression was observed in heart and skeletal muscle. Sequence analysis of a 3-kb cDNA contig revealed an 807-bp open reading frame encoding a putative 268-amino acid protein. Comparison of the sequence with sequences in databases revealed homology with holocytochrome c-type synthetases. The human gene, symbolized HCCS, and the corresponding murine gene characterized by <a href="#4" class="mim-tip-reference" title="Schaefer, L., Ballabio, A., Zoghbi, H. Y. <strong>Cloning and characterization of a putative human holocytochrome c-type synthetase gene (HCCS) isolated from the critical region for microphthalmia with linear skin defects (MLS).</strong> Genomics 34: 166-172, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8661044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8661044</a>] [<a href="https://doi.org/10.1006/geno.1996.0261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8661044">Schaefer et al. (1996)</a> share 83% nucleotide sequence identity and 85% amino acid identity. The authors stated that, because of the lack of a neuromuscular phenotype in MLS, it is uncertain how the deletion of a mitochondrial holocytochrome synthetase would contribute to the phenotype seen in MLS. The expression pattern of the gene and knowledge of the function of holocytochrome synthetases suggested, however, that it is a good candidate for X-linked encephalomyopathies typically associated with mitochondrial dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8661044" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The HCCS gene contains 7 exons and spans 11 kb (<a href="#5" class="mim-tip-reference" title="Van den Veyver, I. B., Subramanian, S., Zoghbi, H. Y. <strong>Genomic structure of a human holocytochrome c-type synthetase gene in Xp22.3 and mutation analysis in patients with Rett syndrome.</strong> Am. J. Med. Genet. 78: 179-181, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9674913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9674913</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19980630)78:2<179::aid-ajmg17>3.3.co;2-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9674913">Van den Veyver et al., 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9674913" 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="#4" class="mim-tip-reference" title="Schaefer, L., Ballabio, A., Zoghbi, H. Y. <strong>Cloning and characterization of a putative human holocytochrome c-type synthetase gene (HCCS) isolated from the critical region for microphthalmia with linear skin defects (MLS).</strong> Genomics 34: 166-172, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8661044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8661044</a>] [<a href="https://doi.org/10.1006/geno.1996.0261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8661044">Schaefer et al. (1996)</a> mapped the HCCS gene to chromosome Xp22 by sequence analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8661044" 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 expression of wildtype and mutant human HCCS in yeast, <a href="#1" class="mim-tip-reference" title="Indrieri, A., Conte, I., Chesi, G., Romano, A., Quartararo, J., Tate, R., Ghezzi, D., Zeviani, M., Goffrini, P., Ferrero, I., Bovolenta, P., Franco, B. <strong>The impairment of HCCS leads to MLS syndrome by activating a non-canonical cell death pathway in the brain and eyes.</strong> EMBO Molec. Med. 5: 280-293, 2013. Note: Erratum: EMBO Molec. Med. 6: 849 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23239471/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23239471</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23239471[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/10.1002/emmm.201201739" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23239471">Indrieri et al. (2013)</a> found that the heme lyase activity of HCCS was not required for HCCS-dependent transport of Cytc into mitochondria. They concluded that binding of HCCS to apo-Cytc, rather than heme attachment, is critical for Cytc import into mitochondria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23239471" 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="#6" class="mim-tip-reference" title="Wimplinger, I., Morleo, M., Rosenberger, G., Iaconis, D., Orth, U., Meinecke, P., Lerer, I., Ballabio, A., Gal, A., Franco, B., Kutsche, K. <strong>Mutations of the mitochondrial holocytochrome c-type synthase in X-linked dominant microphthalmia with linear skin defects syndrome.</strong> Am. J. Hum. Genet. 79: 878-889, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17033964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17033964</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17033964[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/508474" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17033964">Wimplinger et al. (2006)</a> investigated a family with microphthalmia with linear skin defects (LSDMCA1, MLS; <a href="/entry/309801">309801</a>) displaying phenotypic variability in which the youngest daughter, who had a classic phenotype and normal karyotype, had previously been studied by <a href="#2" class="mim-tip-reference" title="Morleo, M., Pramparo, T., Perone, L., Gregato, G., Le Caignec, C., Mueller, R. F., Ogata, T., Raas-Rothschild, A., de Blois, M. C., Wilson, L. C., Zaidman, G., Zuffardi, O., Ballabio, A., Franco, B. <strong>Microphthalmia with linear skin defects (MLS) syndrome: clinical, cytogenetic, and molecular characterization of 11 cases.</strong> Am. J. Med. Genet. 137A: 190-198, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16059943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16059943</a>] [<a href="https://doi.org/10.1002/ajmg.a.30864" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16059943">Morleo et al. (2005)</a> and no pathogenic mutations found in the MID1, HCCS, or ARHGAP6 genes. DNA analysis revealed the presence of a heterozygous 8.6-kb deletion encompassing part of the HCCS gene (<a href="#0001">300056.0001</a>) in the mother and 2 affected daughters; the deletion was not found in 3 sons or an unaffected daughter. <a href="#6" class="mim-tip-reference" title="Wimplinger, I., Morleo, M., Rosenberger, G., Iaconis, D., Orth, U., Meinecke, P., Lerer, I., Ballabio, A., Gal, A., Franco, B., Kutsche, K. <strong>Mutations of the mitochondrial holocytochrome c-type synthase in X-linked dominant microphthalmia with linear skin defects syndrome.</strong> Am. J. Hum. Genet. 79: 878-889, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17033964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17033964</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17033964[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/508474" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17033964">Wimplinger et al. (2006)</a> performed sequence analysis of the HCCS gene in 2 unrelated girls with MLS and normal karyotypes and identified heterozygosity for a de novo nonsense mutation (R197X, <a href="#0002">300056.0002</a>) and a de novo missense mutation (R217C, <a href="#0003">300056.0003</a>), respectively. All of the affected females had a skewed X-chromosome inactivation pattern in peripheral blood cells. Functional studies demonstrated that both the R197X and the R217C mutant proteins were unable to complement a Saccharomyces cerevisiae mutant deficient for the HCCS ortholog, in contrast to wildtype HCCS. Noting that cytochrome c is the final product of HCCS activity, <a href="#6" class="mim-tip-reference" title="Wimplinger, I., Morleo, M., Rosenberger, G., Iaconis, D., Orth, U., Meinecke, P., Lerer, I., Ballabio, A., Gal, A., Franco, B., Kutsche, K. <strong>Mutations of the mitochondrial holocytochrome c-type synthase in X-linked dominant microphthalmia with linear skin defects syndrome.</strong> Am. J. Hum. Genet. 79: 878-889, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17033964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17033964</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17033964[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/508474" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17033964">Wimplinger et al. (2006)</a> suggested that disturbance of both oxidative phosphorylation and the balance between apoptosis and necrosis, as well as X-inactivation patterns, may contribute to the variable phenotype observed in patients with MLS. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16059943+17033964" 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>Exclusion Studies</em></strong></p><p>
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Based on its chromosomal location and its role in the mitochondrial respiratory chain, HCCS was considered a candidate gene for Rett syndrome (RTT; <a href="/entry/312750">312750</a>). No mutational abnormality of the gene was found in 20 RTT patients (<a href="#5" class="mim-tip-reference" title="Van den Veyver, I. B., Subramanian, S., Zoghbi, H. Y. <strong>Genomic structure of a human holocytochrome c-type synthetase gene in Xp22.3 and mutation analysis in patients with Rett syndrome.</strong> Am. J. Med. Genet. 78: 179-181, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9674913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9674913</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19980630)78:2<179::aid-ajmg17>3.3.co;2-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9674913">Van den Veyver et al., 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9674913" 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="Prakash, S. K., Cormier, T. A., McCall, A. E., Garcia, J. J., Sierra, R., Haupt, B., Zoghbi, H. Y., Van den Veyver, I. B. <strong>Loss of holocytochrome c-type synthetase causes the male lethality of X-linked dominant microphthalmia with linear skin defects (MLS) syndrome.</strong> Hum. Molec. Genet. 11: 3237-3248, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12444108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12444108</a>] [<a href="https://doi.org/10.1093/hmg/11.25.3237" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12444108">Prakash et al. (2002)</a> noted that the human HCCS gene is located entirely inside the critical region defined for MLS. They generated a deletion mutant in the mouse that inactivated Hccs. Ubiquitous deletions generated in vivo led to lethality of hemizygous, homozygous, and heterozygous embryos early in development. This lethality was rescued by expression of the human HCCS gene from a transgenic BAC, resulting in viable homozygous, heterozygous, and hemizygous deleted mice with no apparent phenotype. In the presence of the HCCS transgene, the deletion was easily transmitted to subsequent generations. A single heterozygous deleted female that did not express human HCCS was identified, which is analogous to the low prevalence of the heterozygous MLS deletion in humans. The authors concluded that loss of HCCS causes the male lethality of MLS syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12444108" 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="Indrieri, A., Conte, I., Chesi, G., Romano, A., Quartararo, J., Tate, R., Ghezzi, D., Zeviani, M., Goffrini, P., Ferrero, I., Bovolenta, P., Franco, B. <strong>The impairment of HCCS leads to MLS syndrome by activating a non-canonical cell death pathway in the brain and eyes.</strong> EMBO Molec. Med. 5: 280-293, 2013. Note: Erratum: EMBO Molec. Med. 6: 849 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23239471/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23239471</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23239471[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/10.1002/emmm.201201739" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23239471">Indrieri et al. (2013)</a> showed that morpholino-mediated knockdown of Hccs expression in medaka fish caused microphthalmia, microcephaly, and cardiovascular abnormalities, including failure of heart loop formation and pericardial edema, with death at hatching stage. Hccs-deficient embryos showed reduced complex III activity, whereas complexes I, II, and IV activities were normal. Western blot analysis revealed decreased content of Cytc in morphant embryos. Hccs morphants showed sustained apoptosis in retina compared with controls, leading to microphthalmia. Increased apoptosis was evident in several regions of the central nervous system, leading to microcephaly, but was not seen in other organs, including heart. Elevated apoptosis in Hccs morphants appeared to be due to activation and cytosolic release of caspase-9 (CASP9; <a href="/entry/602234">602234</a>) in the absence of Cytc. Reactive oxygen species (ROS) content was elevated in Hccs morphants, and treatment of morphants with an ROS scavenger countered Casp9 activation and rescued microphthalmia and microcephaly. <a href="#1" class="mim-tip-reference" title="Indrieri, A., Conte, I., Chesi, G., Romano, A., Quartararo, J., Tate, R., Ghezzi, D., Zeviani, M., Goffrini, P., Ferrero, I., Bovolenta, P., Franco, B. <strong>The impairment of HCCS leads to MLS syndrome by activating a non-canonical cell death pathway in the brain and eyes.</strong> EMBO Molec. Med. 5: 280-293, 2013. Note: Erratum: EMBO Molec. Med. 6: 849 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23239471/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23239471</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23239471[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/10.1002/emmm.201201739" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23239471">Indrieri et al. (2013)</a> hypothesized that HCCS inhibits a noncanonical cell death pathway in brain and eye via enhanced mitochondrial ROS production and release of active CASP9. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23239471" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a mother and 2 daughters from a family with microphthalmia and linear skin defects (LSDMCA1; <a href="/entry/309801">309801</a>), <a href="#6" class="mim-tip-reference" title="Wimplinger, I., Morleo, M., Rosenberger, G., Iaconis, D., Orth, U., Meinecke, P., Lerer, I., Ballabio, A., Gal, A., Franco, B., Kutsche, K. <strong>Mutations of the mitochondrial holocytochrome c-type synthase in X-linked dominant microphthalmia with linear skin defects syndrome.</strong> Am. J. Hum. Genet. 79: 878-889, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17033964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17033964</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17033964[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/508474" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17033964">Wimplinger et al. (2006)</a> identified an 8.6-kb deletion encompassing exons 1 and 2 and the first 83 bp of exon 3 of the HCCS gene. The youngest daughter, who had a classic phenotype and normal karyotype, had previously been studied by <a href="#2" class="mim-tip-reference" title="Morleo, M., Pramparo, T., Perone, L., Gregato, G., Le Caignec, C., Mueller, R. F., Ogata, T., Raas-Rothschild, A., de Blois, M. C., Wilson, L. C., Zaidman, G., Zuffardi, O., Ballabio, A., Franco, B. <strong>Microphthalmia with linear skin defects (MLS) syndrome: clinical, cytogenetic, and molecular characterization of 11 cases.</strong> Am. J. Med. Genet. 137A: 190-198, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16059943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16059943</a>] [<a href="https://doi.org/10.1002/ajmg.a.30864" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16059943">Morleo et al. (2005)</a> and no pathogenic mutations found in the MID1, HCCS, or ARHGAP6 genes. The eldest daughter of the family had a milder phenotype; and the mother, who had no obvious signs of MLS, had a history of skin lesions in infancy that disappeared over time. The deletion was not found in 3 sons or an unaffected daughter. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16059943+17033964" 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">rs121917888 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917888;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=rs121917888" 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=rs121917888" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 5-year-old girl with microphthalmia with linear skin defects syndrome (LSDMCA1; <a href="/entry/309801">309801</a>), <a href="#6" class="mim-tip-reference" title="Wimplinger, I., Morleo, M., Rosenberger, G., Iaconis, D., Orth, U., Meinecke, P., Lerer, I., Ballabio, A., Gal, A., Franco, B., Kutsche, K. <strong>Mutations of the mitochondrial holocytochrome c-type synthase in X-linked dominant microphthalmia with linear skin defects syndrome.</strong> Am. J. Hum. Genet. 79: 878-889, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17033964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17033964</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17033964[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/508474" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17033964">Wimplinger et al. (2006)</a> identified heterozygosity for a de novo 589C-T transition in exon 6 of the HCCS gene, resulting in an arg197-to-ter (R197X) substitution. The mutation was not found in 50 female controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17033964" 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">rs121917889 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917889;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=rs121917889" 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=rs121917889" 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=RCV000020632 OR RCV003398486" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000020632, RCV003398486" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000020632...</a>
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<p>In a 9-year-old girl with microphthalmia and linear skin defects (LSDMCA1; <a href="/entry/309801">309801</a>), <a href="#6" class="mim-tip-reference" title="Wimplinger, I., Morleo, M., Rosenberger, G., Iaconis, D., Orth, U., Meinecke, P., Lerer, I., Ballabio, A., Gal, A., Franco, B., Kutsche, K. <strong>Mutations of the mitochondrial holocytochrome c-type synthase in X-linked dominant microphthalmia with linear skin defects syndrome.</strong> Am. J. Hum. Genet. 79: 878-889, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17033964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17033964</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17033964[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/508474" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17033964">Wimplinger et al. (2006)</a> identified heterozygosity for a de novo 649C-T transition in exon 7 of the HCCS gene, resulting in an arg217-to-cys (R217C) substitution. The mutation was not found in 110 female controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17033964" 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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Indrieri, A., Conte, I., Chesi, G., Romano, A., Quartararo, J., Tate, R., Ghezzi, D., Zeviani, M., Goffrini, P., Ferrero, I., Bovolenta, P., Franco, B.
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<strong>The impairment of HCCS leads to MLS syndrome by activating a non-canonical cell death pathway in the brain and eyes.</strong>
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EMBO Molec. Med. 5: 280-293, 2013. Note: Erratum: EMBO Molec. Med. 6: 849 only, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23239471/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23239471</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23239471[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=23239471" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Morleo, M., Pramparo, T., Perone, L., Gregato, G., Le Caignec, C., Mueller, R. F., Ogata, T., Raas-Rothschild, A., de Blois, M. C., Wilson, L. C., Zaidman, G., Zuffardi, O., Ballabio, A., Franco, B.
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<strong>Microphthalmia with linear skin defects (MLS) syndrome: clinical, cytogenetic, and molecular characterization of 11 cases.</strong>
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Am. J. Med. Genet. 137A: 190-198, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16059943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16059943</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16059943" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.30864" target="_blank">Full Text</a>]
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<a id="Prakash2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Prakash, S. K., Cormier, T. A., McCall, A. E., Garcia, J. J., Sierra, R., Haupt, B., Zoghbi, H. Y., Van den Veyver, I. B.
|
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<strong>Loss of holocytochrome c-type synthetase causes the male lethality of X-linked dominant microphthalmia with linear skin defects (MLS) syndrome.</strong>
|
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Hum. Molec. Genet. 11: 3237-3248, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12444108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12444108</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12444108" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/11.25.3237" 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="4" class="mim-anchor"></a>
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<a id="Schaefer1996" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Schaefer, L., Ballabio, A., Zoghbi, H. Y.
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<strong>Cloning and characterization of a putative human holocytochrome c-type synthetase gene (HCCS) isolated from the critical region for microphthalmia with linear skin defects (MLS).</strong>
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Genomics 34: 166-172, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8661044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8661044</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8661044" 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/10.1006/geno.1996.0261" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="5" class="mim-anchor"></a>
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<a id="Van den Veyver1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Van den Veyver, I. B., Subramanian, S., Zoghbi, H. Y.
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<strong>Genomic structure of a human holocytochrome c-type synthetase gene in Xp22.3 and mutation analysis in patients with Rett syndrome.</strong>
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Am. J. Med. Genet. 78: 179-181, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9674913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9674913</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9674913" 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)1096-8628(19980630)78:2<179::aid-ajmg17>3.3.co;2-3" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="6" class="mim-anchor"></a>
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<a id="Wimplinger2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wimplinger, I., Morleo, M., Rosenberger, G., Iaconis, D., Orth, U., Meinecke, P., Lerer, I., Ballabio, A., Gal, A., Franco, B., Kutsche, K.
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<strong>Mutations of the mitochondrial holocytochrome c-type synthase in X-linked dominant microphthalmia with linear skin defects syndrome.</strong>
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Am. J. Hum. Genet. 79: 878-889, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17033964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17033964</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17033964[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=17033964" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/508474" target="_blank">Full Text</a>]
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</p>
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</ol>
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<a id="contributors" class="mim-anchor"></a>
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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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<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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Matthew B. Gross - updated : 05/13/2016
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</span>
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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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Patricia A. Hartz - updated : 5/13/2016<br>Marla J. F. O'Neill - updated : 10/10/2006<br>Victor A. McKusick - updated : 10/10/2006<br>George E. Tiller - updated : 9/2/2004<br>Victor A. McKusick - updated : 9/3/1998
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</span>
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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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Victor A. McKusick : 6/25/1996
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</span>
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</div>
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<a id="editHistory" class="mim-anchor"></a>
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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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alopez : 08/12/2016
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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">
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mgross : 05/13/2016<br>mgross : 5/13/2016<br>carol : 5/13/2015<br>carol : 12/14/2012<br>carol : 10/10/2006<br>terry : 10/10/2006<br>carol : 9/3/2004<br>carol : 9/3/2004<br>terry : 9/2/2004<br>alopez : 9/8/1998<br>terry : 9/3/1998<br>mark : 6/25/1996<br>mark : 6/25/1996<br>mark : 6/25/1996
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</span>
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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="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">
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<strong>*</strong> 300056
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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HOLOCYTOCHROME C SYNTHASE; HCCS
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: HCCS</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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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 721879006;
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</span>
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</p>
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<div>
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<br />
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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: Xp22.2
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Genomic coordinates <span class="small">(GRCh38)</span> : X:11,111,332-11,123,086 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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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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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed 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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</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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<tbody>
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<td rowspan="1">
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<span class="mim-font">
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Xp22.2
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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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Linear skin defects with multiple congenital anomalies 1
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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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309801
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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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X-linked dominant
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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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3
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</span>
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</td>
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</tbody>
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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>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>HCCS is a highly conserved gene from fungi to metazoans that encodes holocytochrome c-type synthase, which is located on the outer surface of the inner mitochondrial membrane. HCCS catalyzes covalent attachment of heme to both cytochrome c (CYTC, or CYCS; 123970) and cytochrome c1 (CYTC1, or CYC1; 123980), which are crucial components of the mitochondrial respiratory chain (summary by Indrieri et al., 2013). </p>
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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>Cloning and Expression</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>Using a cross-species conservation strategy, Schaefer et al. (1996) isolated an expressed sequence from a 450- to 550-kb critical region for a microphthalmia syndrome with linear skin defects (LSDMCA1, MLS; 309801) on Xp22 by screening a human embryo cDNA library. Northern analysis demonstrated a transcript of approximately 2.6 kb in all tissues examined, with weaker expression of 1.2- and 5.2-kb transcripts. The strongest expression was observed in heart and skeletal muscle. Sequence analysis of a 3-kb cDNA contig revealed an 807-bp open reading frame encoding a putative 268-amino acid protein. Comparison of the sequence with sequences in databases revealed homology with holocytochrome c-type synthetases. The human gene, symbolized HCCS, and the corresponding murine gene characterized by Schaefer et al. (1996) share 83% nucleotide sequence identity and 85% amino acid identity. The authors stated that, because of the lack of a neuromuscular phenotype in MLS, it is uncertain how the deletion of a mitochondrial holocytochrome synthetase would contribute to the phenotype seen in MLS. The expression pattern of the gene and knowledge of the function of holocytochrome synthetases suggested, however, that it is a good candidate for X-linked encephalomyopathies typically associated with mitochondrial dysfunction. </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>Gene Structure</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>The HCCS gene contains 7 exons and spans 11 kb (Van den Veyver et al., 1998). </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>Mapping</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>Schaefer et al. (1996) mapped the HCCS gene to chromosome Xp22 by sequence analysis. </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>Gene Function</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>By expression of wildtype and mutant human HCCS in yeast, Indrieri et al. (2013) found that the heme lyase activity of HCCS was not required for HCCS-dependent transport of Cytc into mitochondria. They concluded that binding of HCCS to apo-Cytc, rather than heme attachment, is critical for Cytc import into mitochondria. </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>Molecular Genetics</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>Wimplinger et al. (2006) investigated a family with microphthalmia with linear skin defects (LSDMCA1, MLS; 309801) displaying phenotypic variability in which the youngest daughter, who had a classic phenotype and normal karyotype, had previously been studied by Morleo et al. (2005) and no pathogenic mutations found in the MID1, HCCS, or ARHGAP6 genes. DNA analysis revealed the presence of a heterozygous 8.6-kb deletion encompassing part of the HCCS gene (300056.0001) in the mother and 2 affected daughters; the deletion was not found in 3 sons or an unaffected daughter. Wimplinger et al. (2006) performed sequence analysis of the HCCS gene in 2 unrelated girls with MLS and normal karyotypes and identified heterozygosity for a de novo nonsense mutation (R197X, 300056.0002) and a de novo missense mutation (R217C, 300056.0003), respectively. All of the affected females had a skewed X-chromosome inactivation pattern in peripheral blood cells. Functional studies demonstrated that both the R197X and the R217C mutant proteins were unable to complement a Saccharomyces cerevisiae mutant deficient for the HCCS ortholog, in contrast to wildtype HCCS. Noting that cytochrome c is the final product of HCCS activity, Wimplinger et al. (2006) suggested that disturbance of both oxidative phosphorylation and the balance between apoptosis and necrosis, as well as X-inactivation patterns, may contribute to the variable phenotype observed in patients with MLS. </p><p><strong><em>Exclusion Studies</em></strong></p><p>
|
|
Based on its chromosomal location and its role in the mitochondrial respiratory chain, HCCS was considered a candidate gene for Rett syndrome (RTT; 312750). No mutational abnormality of the gene was found in 20 RTT patients (Van den Veyver et al., 1998). </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">
|
|
<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>Prakash et al. (2002) noted that the human HCCS gene is located entirely inside the critical region defined for MLS. They generated a deletion mutant in the mouse that inactivated Hccs. Ubiquitous deletions generated in vivo led to lethality of hemizygous, homozygous, and heterozygous embryos early in development. This lethality was rescued by expression of the human HCCS gene from a transgenic BAC, resulting in viable homozygous, heterozygous, and hemizygous deleted mice with no apparent phenotype. In the presence of the HCCS transgene, the deletion was easily transmitted to subsequent generations. A single heterozygous deleted female that did not express human HCCS was identified, which is analogous to the low prevalence of the heterozygous MLS deletion in humans. The authors concluded that loss of HCCS causes the male lethality of MLS syndrome. </p><p>Indrieri et al. (2013) showed that morpholino-mediated knockdown of Hccs expression in medaka fish caused microphthalmia, microcephaly, and cardiovascular abnormalities, including failure of heart loop formation and pericardial edema, with death at hatching stage. Hccs-deficient embryos showed reduced complex III activity, whereas complexes I, II, and IV activities were normal. Western blot analysis revealed decreased content of Cytc in morphant embryos. Hccs morphants showed sustained apoptosis in retina compared with controls, leading to microphthalmia. Increased apoptosis was evident in several regions of the central nervous system, leading to microcephaly, but was not seen in other organs, including heart. Elevated apoptosis in Hccs morphants appeared to be due to activation and cytosolic release of caspase-9 (CASP9; 602234) in the absence of Cytc. Reactive oxygen species (ROS) content was elevated in Hccs morphants, and treatment of morphants with an ROS scavenger countered Casp9 activation and rescued microphthalmia and microcephaly. Indrieri et al. (2013) hypothesized that HCCS inhibits a noncanonical cell death pathway in brain and eye via enhanced mitochondrial ROS production and release of active CASP9. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>3 Selected Examples):</strong>
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<strong>.0001 LINEAR SKIN DEFECTS WITH MULTIPLE CONGENITAL ANOMALIES 1</strong>
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</h4>
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HCCS, 8.6-KB DEL
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ClinVar: RCV000012435
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<p>In a mother and 2 daughters from a family with microphthalmia and linear skin defects (LSDMCA1; 309801), Wimplinger et al. (2006) identified an 8.6-kb deletion encompassing exons 1 and 2 and the first 83 bp of exon 3 of the HCCS gene. The youngest daughter, who had a classic phenotype and normal karyotype, had previously been studied by Morleo et al. (2005) and no pathogenic mutations found in the MID1, HCCS, or ARHGAP6 genes. The eldest daughter of the family had a milder phenotype; and the mother, who had no obvious signs of MLS, had a history of skin lesions in infancy that disappeared over time. The deletion was not found in 3 sons or an unaffected daughter. </p>
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<span class="mim-font">
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<strong>.0002 LINEAR SKIN DEFECTS WITH MULTIPLE CONGENITAL ANOMALIES 1</strong>
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HCCS, ARG197TER
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<br />
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SNP: rs121917888,
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ClinVar: RCV000020631
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<p>In a 5-year-old girl with microphthalmia with linear skin defects syndrome (LSDMCA1; 309801), Wimplinger et al. (2006) identified heterozygosity for a de novo 589C-T transition in exon 6 of the HCCS gene, resulting in an arg197-to-ter (R197X) substitution. The mutation was not found in 50 female controls. </p>
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<h4>
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<span class="mim-font">
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<strong>.0003 LINEAR SKIN DEFECTS WITH MULTIPLE CONGENITAL ANOMALIES 1</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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HCCS, ARG217CYS
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<br />
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SNP: rs121917889,
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ClinVar: RCV000020632, RCV003398486
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<span class="mim-text-font">
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<p>In a 9-year-old girl with microphthalmia and linear skin defects (LSDMCA1; 309801), Wimplinger et al. (2006) identified heterozygosity for a de novo 649C-T transition in exon 7 of the HCCS gene, resulting in an arg217-to-cys (R217C) substitution. The mutation was not found in 110 female controls. </p>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</h4>
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Indrieri, A., Conte, I., Chesi, G., Romano, A., Quartararo, J., Tate, R., Ghezzi, D., Zeviani, M., Goffrini, P., Ferrero, I., Bovolenta, P., Franco, B.
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<strong>The impairment of HCCS leads to MLS syndrome by activating a non-canonical cell death pathway in the brain and eyes.</strong>
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EMBO Molec. Med. 5: 280-293, 2013. Note: Erratum: EMBO Molec. Med. 6: 849 only, 2014.
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[PubMed: 23239471]
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[Full Text: https://doi.org/10.1002/emmm.201201739]
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</li>
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<li>
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<p class="mim-text-font">
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Morleo, M., Pramparo, T., Perone, L., Gregato, G., Le Caignec, C., Mueller, R. F., Ogata, T., Raas-Rothschild, A., de Blois, M. C., Wilson, L. C., Zaidman, G., Zuffardi, O., Ballabio, A., Franco, B.
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<strong>Microphthalmia with linear skin defects (MLS) syndrome: clinical, cytogenetic, and molecular characterization of 11 cases.</strong>
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Am. J. Med. Genet. 137A: 190-198, 2005.
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[PubMed: 16059943]
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[Full Text: https://doi.org/10.1002/ajmg.a.30864]
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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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Prakash, S. K., Cormier, T. A., McCall, A. E., Garcia, J. J., Sierra, R., Haupt, B., Zoghbi, H. Y., Van den Veyver, I. B.
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<strong>Loss of holocytochrome c-type synthetase causes the male lethality of X-linked dominant microphthalmia with linear skin defects (MLS) syndrome.</strong>
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Hum. Molec. Genet. 11: 3237-3248, 2002.
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[PubMed: 12444108]
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[Full Text: https://doi.org/10.1093/hmg/11.25.3237]
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</p>
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<li>
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<p class="mim-text-font">
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Schaefer, L., Ballabio, A., Zoghbi, H. Y.
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<strong>Cloning and characterization of a putative human holocytochrome c-type synthetase gene (HCCS) isolated from the critical region for microphthalmia with linear skin defects (MLS).</strong>
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Genomics 34: 166-172, 1996.
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[PubMed: 8661044]
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[Full Text: https://doi.org/10.1006/geno.1996.0261]
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</p>
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<li>
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<p class="mim-text-font">
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Van den Veyver, I. B., Subramanian, S., Zoghbi, H. Y.
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<strong>Genomic structure of a human holocytochrome c-type synthetase gene in Xp22.3 and mutation analysis in patients with Rett syndrome.</strong>
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Am. J. Med. Genet. 78: 179-181, 1998.
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[PubMed: 9674913]
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[Full Text: https://doi.org/10.1002/(sici)1096-8628(19980630)78:2<179::aid-ajmg17>3.3.co;2-3]
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</p>
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<li>
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<p class="mim-text-font">
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Wimplinger, I., Morleo, M., Rosenberger, G., Iaconis, D., Orth, U., Meinecke, P., Lerer, I., Ballabio, A., Gal, A., Franco, B., Kutsche, K.
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<strong>Mutations of the mitochondrial holocytochrome c-type synthase in X-linked dominant microphthalmia with linear skin defects syndrome.</strong>
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Am. J. Hum. Genet. 79: 878-889, 2006.
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[PubMed: 17033964]
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[Full Text: https://doi.org/10.1086/508474]
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Contributors:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Matthew B. Gross - updated : 05/13/2016<br>Patricia A. Hartz - updated : 5/13/2016<br>Marla J. F. O'Neill - updated : 10/10/2006<br>Victor A. McKusick - updated : 10/10/2006<br>George E. Tiller - updated : 9/2/2004<br>Victor A. McKusick - updated : 9/3/1998
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<span class="mim-text-font">
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Victor A. McKusick : 6/25/1996
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alopez : 08/12/2016<br>mgross : 05/13/2016<br>mgross : 5/13/2016<br>carol : 5/13/2015<br>carol : 12/14/2012<br>carol : 10/10/2006<br>terry : 10/10/2006<br>carol : 9/3/2004<br>carol : 9/3/2004<br>terry : 9/2/2004<br>alopez : 9/8/1998<br>terry : 9/3/1998<br>mark : 6/25/1996<br>mark : 6/25/1996<br>mark : 6/25/1996
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