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Entry
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- *614725 - SERINE ACTIVE SITE-CONTAINING PROTEIN 1; SERAC1
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- OMIM
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<p>
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<span class="h4">*614725</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</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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<a href="#molecularGenetics">Molecular Genetics</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/614725">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div class="panel 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=ENSG00000122335;t=ENST00000647468" 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=84947" 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=614725" 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=ENSG00000122335;t=ENST00000647468" 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_032861,NR_073096,XM_006715586,XM_011536198,XM_024446573,XM_047419421,XR_007059349" 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_032861" 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=614725" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.proteinatlas.org/search/SERAC1" 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/14042785,37515274,71296743,74751971,119568049,228008407,578813023,767943747,1370508808,2217363330,2462610947,2462610949,2462610951,2462610953" 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/Q96JX3" 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=84947" 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=ENSG00000122335;t=ENST00000647468" 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=SERAC1" 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=SERAC1" 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+84947" 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/SERAC1" 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:84947" 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/84947" 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=chr6&hgg_gene=ENST00000647468.2&hgg_start=158109519&hgg_end=158168262&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:21061" 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://search.clinicalgenome.org/kb/genes/HGNC:21061" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/serac1" 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=614725[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=614725[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000122335" 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=SERAC1" 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=SERAC1" 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=SERAC1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=SERAC1&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/PA134951844" 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:21061" 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/FBgn0032699.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:2447813" 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/SERAC1#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:2447813" 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/84947/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://omia.org/OMIA001468/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=84947" 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=WBGene00008925;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-040616-1" 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://reactome.org/content/query?q=SERAC1&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> 711409002<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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614725
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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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SERINE ACTIVE SITE-CONTAINING PROTEIN 1; SERAC1
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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=SERAC1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SERAC1</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/6/982?start=-3&limit=10&highlight=982">6q25.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr6:158109519-158168262&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'})">6:158,109,519-158,168,262</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/6/982?start=-3&limit=10&highlight=982">
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6q25.3
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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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3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome
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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/614739"> 614739 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</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/614725" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/614725" 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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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div>
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<a id="description" class="mim-anchor"></a>
|
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<p>SERAC1 functions in phosphatidylglycerol remodeling that is essential for mitochondrial function and intracellular cholesterol trafficking (<a href="#7" class="mim-tip-reference" title="Wortmann, S. B., Vaz, F. M., Gardeitchik, T., Vissers, L. E. L. M., Renkema, G. H., Schuurs-Hoeijmakers, J. H. M., Kulik, W., Lammens, M., Christin, C., Kluijtmans, L. A. J., Rodenburg, R. J., Nijtmans, L. G. J., and 22 others. <strong>Mutations in the phospholipid remodeling gene SERCA1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness.</strong> Nature Genet. 44: 797-802, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22683713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22683713</a>] [<a href="https://doi.org/10.1038/ng.2325" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22683713">Wortmann et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22683713" 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="#7" class="mim-tip-reference" title="Wortmann, S. B., Vaz, F. M., Gardeitchik, T., Vissers, L. E. L. M., Renkema, G. H., Schuurs-Hoeijmakers, J. H. M., Kulik, W., Lammens, M., Christin, C., Kluijtmans, L. A. J., Rodenburg, R. J., Nijtmans, L. G. J., and 22 others. <strong>Mutations in the phospholipid remodeling gene SERCA1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness.</strong> Nature Genet. 44: 797-802, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22683713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22683713</a>] [<a href="https://doi.org/10.1038/ng.2325" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22683713">Wortmann et al. (2012)</a> reported that the deduced SERAC1 protein has an N-terminal signal sequence and a C-terminal serine-lipase/esterase domain containing the consensus lipase motif GxSxG. Quantitative PCR analysis detected variable SERAC1 expression in all adult and fetal tissues examined, with highest expression in fetal skeletal muscle, followed by adult brain, fetal heart, and fetal kidney. Expression in fetal brain was much lower than that in adult brain. SERAC1 was detected in all specific adult brain regions examined, with highest expression in occipital cortex, followed by frontal cortex, cerebellum, and hippocampus. Western blot analysis of fractionated human fibroblasts and immunohistochemical analysis showed SERAC1 localization in both mitochondria and endoplasmic reticulum in a pattern consistent with enrichment in the mitochondria-associated membranes. Database analysis identified SERAC1 orthologs in all eukaryotes examined, with highest conservation in the lipase domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22683713" 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 15 individuals from 13 families with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; <a href="/entry/614739">614739</a>), which is also referred to as 3-methylglutaconic aciduria type VI (MGCA6), <a href="#7" class="mim-tip-reference" title="Wortmann, S. B., Vaz, F. M., Gardeitchik, T., Vissers, L. E. L. M., Renkema, G. H., Schuurs-Hoeijmakers, J. H. M., Kulik, W., Lammens, M., Christin, C., Kluijtmans, L. A. J., Rodenburg, R. J., Nijtmans, L. G. J., and 22 others. <strong>Mutations in the phospholipid remodeling gene SERCA1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness.</strong> Nature Genet. 44: 797-802, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22683713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22683713</a>] [<a href="https://doi.org/10.1038/ng.2325" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22683713">Wortmann et al. (2012)</a> identified 14 different homozygous or compound heterozygous mutations in the SERAC1 gene (see, e.g., <a href="#0001">614725.0001</a>-<a href="#0005">614725.0005</a>). The first 2 mutations were identified by exome sequencing and confirmed by Sanger sequencing. The patients had psychomotor retardation, spasticity and/or dystonia, deafness, and brain lesions on MRI. Laboratory studies showed increased serum lactate and alanine, urinary 3-MGA, mitochondrial oxidative phosphorylation defects, abnormal mitochondria, an abnormal phosphatidylglycerol and cardiolipin spectrum in fibroblasts, and abnormal accumulation of unesterified cholesterol within cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22683713" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with MEGDEL, <a href="#6" class="mim-tip-reference" title="Tort, F., Garcia-Silva, M. T., Ferrer-Cortes, X., Navarro-Sastre, A., Garcia-Villoria, J., Coll, M. J., Vidal, E., Jimenez-Almazan, J., Dopazo, J., Briones, P., Elpeleg, O., Ribes, A. <strong>Exome sequencing identifies a new mutation in SERAC1 in a patient with 3-methylglutaconic aciduria.</strong> Molec. Genet. Metab. 110: 73-77, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23707711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23707711</a>] [<a href="https://doi.org/10.1016/j.ymgme.2013.04.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23707711">Tort et al. (2013)</a> identified a homozygous truncating mutation in the SERAC1 gene (R68X; <a href="#0006">614725.0006</a>). The mutation was found by exome sequencing and segregated with the disorder in the family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23707711" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 67 patients with MEGDEL, including 39 previously unreported individuals, <a href="#3" class="mim-tip-reference" title="Maas, R. R., Iwanicka-Pronicka, K., Kalkan Ucar, S., Alhaddad, B., AlSayed, M., Al-Owain, M. A., Al-Zaidan, H. I., Balasubramaniam, S., Baric, I., Bubshait, D. K., Burlina, A., Christodoulou, J., and 46 others. <strong>Progressive deafness-dystonia due to SERAC1 mutations: a study of 67 cases.</strong> Ann. Neurol. 82: 1004-1015, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29205472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29205472</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29205472[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/ana.25110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29205472">Maas et al. (2017)</a> identified 41 SERAC1 sequence variants, including 20 novel variants. (<a href="#3" class="mim-tip-reference" title="Maas, R. R., Iwanicka-Pronicka, K., Kalkan Ucar, S., Alhaddad, B., AlSayed, M., Al-Owain, M. A., Al-Zaidan, H. I., Balasubramaniam, S., Baric, I., Bubshait, D. K., Burlina, A., Christodoulou, J., and 46 others. <strong>Progressive deafness-dystonia due to SERAC1 mutations: a study of 67 cases.</strong> Ann. Neurol. 82: 1004-1015, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29205472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29205472</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29205472[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/ana.25110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29205472">Maas et al. (2017)</a> used the acronym MEGDHEL to include the clinical feature of hepatopathy.) The mutations were located throughout the gene, with no hotspots, although there were several recurrent mutations, suggesting founder effects in certain populations. Most of the mutations were predicted to result in a loss of function, suggesting that missense mutations may be better tolerated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29205472" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated Indian patients, born to consanguineous parents, with MEGDEL, <a href="#4" class="mim-tip-reference" title="Rama Devi, A. R., Lingappa, L. <strong>Novel mutations in SERAC1 gene in two Indian patients presenting with dystonia and intellectual disability.</strong> Europ. J. Med. Genet. 61: 100-103, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28778788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28778788</a>] [<a href="https://doi.org/10.1016/j.ejmg.2017.07.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28778788">Rama Devi and Lingappa (2018)</a> identified homozygous mutations in the SERAC1 gene (<a href="#0008">614725.0008</a> and <a href="#0009">614725.0009</a>). The mutations were found by whole-exome sequencing. In 1 family, the parents were confirmed by Sanger sequencing to be carriers; in the other family, the parents refused to be sequenced. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28778788" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a Saudi Arabian boy with MEGDEL, <a href="#2" class="mim-tip-reference" title="Lumish, H. S., Yang, Y., Xia, F., Wilson, A., Chung, W. K. <strong>The expanding MEGDEL phenotype: optic nerve atrophy, microcephaly, and myoclonic epilepsy in a child with SERAC1 mutations.</strong> JIMD Rep. 16: 75-79, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24997715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24997715</a>] [<a href="https://doi.org/10.1007/8904_2014_322" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24997715">Lumish et al. (2014)</a> identified compound heterozygous mutations in the SERAC1 gene (<a href="#0001">614725.0001</a> and <a href="#0010">614725.0010</a>). The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. The father carried one of the mutations; the mother's status was not given. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24997715" 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 3 members of a consanguineous Turkish family with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; <a href="/entry/614739">614739</a>), <a href="#7" class="mim-tip-reference" title="Wortmann, S. B., Vaz, F. M., Gardeitchik, T., Vissers, L. E. L. M., Renkema, G. H., Schuurs-Hoeijmakers, J. H. M., Kulik, W., Lammens, M., Christin, C., Kluijtmans, L. A. J., Rodenburg, R. J., Nijtmans, L. G. J., and 22 others. <strong>Mutations in the phospholipid remodeling gene SERCA1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness.</strong> Nature Genet. 44: 797-802, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22683713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22683713</a>] [<a href="https://doi.org/10.1038/ng.2325" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22683713">Wortmann et al. (2012)</a> identified a homozygous 442C-T transition in the SERAC1 gene, resulting in an arg148-to-ter (R148X) substitution. The mutation was identified by exome sequencing and confirmed by Sanger sequencing, and was not found in 369 controls. The index patient had previously been reported as patient 3 by <a href="#8" class="mim-tip-reference" title="Wortmann, S., Rodenburg, R. J. T., Huizing, M., Loupatty, F. J., de Koning, T., Kluijtmans, L. A. J., Engelke, U., Wevers, R., Smeitink, J. A. M., Morava, E. <strong>Association of 3-methylglutaconic aciduria with sensori-neural deafness, encephalopathy, and Leigh-like syndrome (MEGDEL association) in four patients with a disorder of the oxidative phosphorylation.</strong> Molec. Genet. Metab. 88: 47-52, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16527507/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16527507</a>] [<a href="https://doi.org/10.1016/j.ymgme.2006.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16527507">Wortmann et al. (2006)</a>. Clinical features included psychomotor retardation, recurrent infections in infancy, hypoglycemia, spasticity, dystonia, sensorineural deafness, brain atrophy, and lesions on brain imaging. Laboratory studies showed increased serum lactate and alanine, urinary 3-MGA, mitochondrial oxidative phosphorylation defects, abnormal mitochondria, an abnormal phosphatidylglycerol and cardiolipin spectrum in fibroblasts, and abnormal accumulation of unesterified cholesterol within cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22683713+16527507" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a Saudi Arabian patient with MEGDEL, <a href="#2" class="mim-tip-reference" title="Lumish, H. S., Yang, Y., Xia, F., Wilson, A., Chung, W. K. <strong>The expanding MEGDEL phenotype: optic nerve atrophy, microcephaly, and myoclonic epilepsy in a child with SERAC1 mutations.</strong> JIMD Rep. 16: 75-79, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24997715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24997715</a>] [<a href="https://doi.org/10.1007/8904_2014_322" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24997715">Lumish et al. (2014)</a> identified compound heterozygous mutations in the SERAC1 gene: R148X and a 1-bp deletion (c.438delC; <a href="#0010">614725.0010</a>) in the SERAC1 gene, predicted to result in a frameshift and premature termination (Thr147fsTer22). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The patient's father was shown to be a carrier of the c.438delC mutation. The c.438delC mutation was not present in the 1000 Genomes Project and EVS databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24997715" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1131690799 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1131690799;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs1131690799?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1131690799" 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=rs1131690799" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 unrelated patients with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; <a href="/entry/614739">614739</a>), <a href="#7" class="mim-tip-reference" title="Wortmann, S. B., Vaz, F. M., Gardeitchik, T., Vissers, L. E. L. M., Renkema, G. H., Schuurs-Hoeijmakers, J. H. M., Kulik, W., Lammens, M., Christin, C., Kluijtmans, L. A. J., Rodenburg, R. J., Nijtmans, L. G. J., and 22 others. <strong>Mutations in the phospholipid remodeling gene SERCA1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness.</strong> Nature Genet. 44: 797-802, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22683713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22683713</a>] [<a href="https://doi.org/10.1038/ng.2325" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22683713">Wortmann et al. (2012)</a> identified a homozygous G-to-C transversion in the donor splice site of exon 13 of the SERAC1 gene (1403+1G-C), resulting in the skipping of exon 13 and nonsense-mediated mRNA decay. One patient was born of consanguineous Pakistani parents and the other of unrelated Indian parents; haplotype analysis suggested a founder effect. The mutation was not found in 369 controls. The patients had psychomotor retardation, spasticity, dystonia, Leigh syndrome-like lesions on brain imaging, and increased urinary 3-MGA. Only 1 had hearing loss. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22683713" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs772296795 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs772296795;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs772296795?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs772296795" 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=rs772296795" 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 Turkish girl, born of consanguineous parents, with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; <a href="/entry/614739">614739</a>), <a href="#7" class="mim-tip-reference" title="Wortmann, S. B., Vaz, F. M., Gardeitchik, T., Vissers, L. E. L. M., Renkema, G. H., Schuurs-Hoeijmakers, J. H. M., Kulik, W., Lammens, M., Christin, C., Kluijtmans, L. A. J., Rodenburg, R. J., Nijtmans, L. G. J., and 22 others. <strong>Mutations in the phospholipid remodeling gene SERCA1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness.</strong> Nature Genet. 44: 797-802, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22683713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22683713</a>] [<a href="https://doi.org/10.1038/ng.2325" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22683713">Wortmann et al. (2012)</a> identified a homozygous 4-bp deletion (1167delTCAG) in a canonical splice site of the SERAC1 gene, resulting in the skipping of exon 12 and nonsense-mediated mRNA decay. The mutation was not found in 369 controls. The patient, who was originally reported as patient 1 by <a href="#8" class="mim-tip-reference" title="Wortmann, S., Rodenburg, R. J. T., Huizing, M., Loupatty, F. J., de Koning, T., Kluijtmans, L. A. J., Engelke, U., Wevers, R., Smeitink, J. A. M., Morava, E. <strong>Association of 3-methylglutaconic aciduria with sensori-neural deafness, encephalopathy, and Leigh-like syndrome (MEGDEL association) in four patients with a disorder of the oxidative phosphorylation.</strong> Molec. Genet. Metab. 88: 47-52, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16527507/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16527507</a>] [<a href="https://doi.org/10.1016/j.ymgme.2006.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16527507">Wortmann et al. (2006)</a>, had recurrent infections, failure to thrive, mental retardation, spasticity and extrapyramidal symptoms, deafness, hypoglycemia, increased serum lactate, abnormal lesions on brain imaging, and oxidative phosphorylation defects. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22683713+16527507" 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 Turkish girl, born of consanguineous parents, with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; <a href="/entry/614739">614739</a>), <a href="#7" class="mim-tip-reference" title="Wortmann, S. B., Vaz, F. M., Gardeitchik, T., Vissers, L. E. L. M., Renkema, G. H., Schuurs-Hoeijmakers, J. H. M., Kulik, W., Lammens, M., Christin, C., Kluijtmans, L. A. J., Rodenburg, R. J., Nijtmans, L. G. J., and 22 others. <strong>Mutations in the phospholipid remodeling gene SERCA1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness.</strong> Nature Genet. 44: 797-802, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22683713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22683713</a>] [<a href="https://doi.org/10.1038/ng.2325" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22683713">Wortmann et al. (2012)</a> identified a homozygous 3-bp deletion (1435delCTT) in the SERAC1 gene, resulting in an in-frame deletion of an amino acid in the highly conserved lipase domain. The patient was originally reported as patient 4 by <a href="#8" class="mim-tip-reference" title="Wortmann, S., Rodenburg, R. J. T., Huizing, M., Loupatty, F. J., de Koning, T., Kluijtmans, L. A. J., Engelke, U., Wevers, R., Smeitink, J. A. M., Morava, E. <strong>Association of 3-methylglutaconic aciduria with sensori-neural deafness, encephalopathy, and Leigh-like syndrome (MEGDEL association) in four patients with a disorder of the oxidative phosphorylation.</strong> Molec. Genet. Metab. 88: 47-52, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16527507/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16527507</a>] [<a href="https://doi.org/10.1016/j.ymgme.2006.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16527507">Wortmann et al. (2006)</a>. The mutation was not found in 369 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22683713+16527507" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs767780913 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs767780913;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs767780913?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs767780913" 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=rs767780913" 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=RCV000029222 OR RCV000195622" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000029222, RCV000195622" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000029222...</a>
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<p>In a Dutch girl with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; <a href="/entry/614739">614739</a>), <a href="#7" class="mim-tip-reference" title="Wortmann, S. B., Vaz, F. M., Gardeitchik, T., Vissers, L. E. L. M., Renkema, G. H., Schuurs-Hoeijmakers, J. H. M., Kulik, W., Lammens, M., Christin, C., Kluijtmans, L. A. J., Rodenburg, R. J., Nijtmans, L. G. J., and 22 others. <strong>Mutations in the phospholipid remodeling gene SERCA1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness.</strong> Nature Genet. 44: 797-802, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22683713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22683713</a>] [<a href="https://doi.org/10.1038/ng.2325" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22683713">Wortmann et al. (2012)</a> identified a homozygous 2-bp duplication (1627dupTC) in the SERAC1 gene, resulting in a frameshift and premature termination (Val544LeufsTer43). The patient was originally reported as patient 2 by <a href="#8" class="mim-tip-reference" title="Wortmann, S., Rodenburg, R. J. T., Huizing, M., Loupatty, F. J., de Koning, T., Kluijtmans, L. A. J., Engelke, U., Wevers, R., Smeitink, J. A. M., Morava, E. <strong>Association of 3-methylglutaconic aciduria with sensori-neural deafness, encephalopathy, and Leigh-like syndrome (MEGDEL association) in four patients with a disorder of the oxidative phosphorylation.</strong> Molec. Genet. Metab. 88: 47-52, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16527507/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16527507</a>] [<a href="https://doi.org/10.1016/j.ymgme.2006.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16527507">Wortmann et al. (2006)</a>. The mutation was not found in 369 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22683713+16527507" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 3-@METHYLGLUTACONIC ACIDURIA WITH DEAFNESS, ENCEPHALOPATHY, AND LEIGH-LIKE SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs529232938 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs529232938;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs529232938?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs529232938" 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=rs529232938" 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 patient with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; <a href="/entry/614739">614739</a>), <a href="#6" class="mim-tip-reference" title="Tort, F., Garcia-Silva, M. T., Ferrer-Cortes, X., Navarro-Sastre, A., Garcia-Villoria, J., Coll, M. J., Vidal, E., Jimenez-Almazan, J., Dopazo, J., Briones, P., Elpeleg, O., Ribes, A. <strong>Exome sequencing identifies a new mutation in SERAC1 in a patient with 3-methylglutaconic aciduria.</strong> Molec. Genet. Metab. 110: 73-77, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23707711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23707711</a>] [<a href="https://doi.org/10.1016/j.ymgme.2013.04.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23707711">Tort et al. (2013)</a> identified a homozygous c.202C-T transition in the SERAC1 gene, resulting in an arg68-to-ter (R68X) substitution. Western blot of patient cells showed no detectable SERAC1 protein. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23707711" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 3-@METHYLGLUTACONIC ACIDURIA WITH DEAFNESS, ENCEPHALOPATHY, AND LEIGH-LIKE SYNDROME, MILD VARIANT</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1554265452 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1554265452;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=rs1554265452" 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=rs1554265452" 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=RCV000578380" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000578380" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000578380</a>
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<p>In 6 members of a large consanguineous Iraqi family with a mild variant of 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; <a href="/entry/614739">614739</a>), <a href="#5" class="mim-tip-reference" title="Roeben, B., Schule, R., Ruf, S., Bender, B., Alhaddad, B., Benkert, T., Meitinger, T., Reich, S., Bohringer, J., Langhans, C.-D., Vaz, F. M., Wortmann, S. B., Marquart, T., Haack, T. B., Krageloh-Mann, I., Schols, L., Synofzik, M. <strong>SERAC1 deficiency causes complicated HSP: evidence from a novel splice mutation in a large family.</strong> J. Med. Genet. 55: 39-47, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28916646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28916646</a>] [<a href="https://doi.org/10.1136/jmedgenet-2017-104622" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28916646">Roeben et al. (2018)</a> identified a homozygous T-to-C transition (c.91+6T-C, NM_032861.3) close to the canonical splice donor of exon 2 in the SERAC1 gene, which is the first coding exon in the transcript. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP (build 142), 1000 Genomes Project, or ExAC (February 2016) databases, or in 8,000 in-house exomes. Analysis of patient cells showed 2 shortened mutant SERAC1 transcripts lacking exon 2 and exons 2 and 3, respectively. There was no suggestion of mRNA decay, but Western blot analysis detected no full-length SERAC1 protein. Patient cells showed impaired phosphatidylglycerol remodeling, although the changes were milder than that observed in other patients with MEGDEL. Correspondingly, the patients presented with juvenile-onset progressive spastic paraplegia and mild cognitive impairment, although none had deafness. The findings expanded the phenotypic spectrum associated with SERAC1 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28916646" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 3-@METHYLGLUTACONIC ACIDURIA WITH DEAFNESS, ENCEPHALOPATHY, AND LEIGH-LIKE SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs761964407 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs761964407;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs761964407?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs761964407" 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=rs761964407" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In an Indian patient, born to consanguineous parents, with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; <a href="/entry/614739">614739</a>), <a href="#4" class="mim-tip-reference" title="Rama Devi, A. R., Lingappa, L. <strong>Novel mutations in SERAC1 gene in two Indian patients presenting with dystonia and intellectual disability.</strong> Europ. J. Med. Genet. 61: 100-103, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28778788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28778788</a>] [<a href="https://doi.org/10.1016/j.ejmg.2017.07.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28778788">Rama Devi and Lingappa (2018)</a> identified homozygosity for a 4-bp duplication (c.1643_1646dupATCT, NM_032861.3) in exon 15 of the SERAC1 gene, predicted to result in a frameshift and premature termination (Leu550fsTer19). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The mutation was not present in the 1000 Genomes Project database and was present in the ExAC database at a minor allele frequency of 0.02%. The patient had a history of neonatal hepatopathy and metabolic acidosis, developmental delay, and dystonia. Urine organic acid analysis in the patient showed elevations of 3-methylglutaconic and 3-methylglutaric acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28778788" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 3-@METHYLGLUTACONIC ACIDURIA WITH DEAFNESS, ENCEPHALOPATHY, AND LEIGH-LIKE SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1554261079 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1554261079;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=rs1554261079" 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=rs1554261079" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In an 11-year-old Indian patient, born of consanguineous parents, with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; <a href="/entry/614739">614739</a>), <a href="#4" class="mim-tip-reference" title="Rama Devi, A. R., Lingappa, L. <strong>Novel mutations in SERAC1 gene in two Indian patients presenting with dystonia and intellectual disability.</strong> Europ. J. Med. Genet. 61: 100-103, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28778788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28778788</a>] [<a href="https://doi.org/10.1016/j.ejmg.2017.07.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28778788">Rama Devi and Lingappa (2018)</a> identified homozygosity for a c.1709G-A transition (c.1709G-A, NM_032861.3) in exon 15 of the SERAC1 gene, resulting in a gly526-to-glu (G526E) substitution. The mutation was identified by whole-exome sequencing. The mutation was not present in the 1000 Genomes Project and ExAC databases. The patient had a history of developmental regression, ataxia, jaundice, and basal ganglia abnormalities on MRI. Urine organic acid analysis in the patient showed mild elevations of 3-methylglutaconic and 3-methylglutaric acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28778788" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 3-@METHYLGLUTACONIC ACIDURIA WITH DEAFNESS, ENCEPHALOPATHY, AND LEIGH-LIKE SYNDROME</strong>
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SERAC1, 1-BP DEL, 438C
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1583595091 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1583595091;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=rs1583595091" 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=rs1583595091" 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=RCV000850598" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000850598" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000850598</a>
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<p>For description of the 1-bp deletion (c.438delC) in the SERAC1 gene, predicted to result in a frameshift and premature termination (Thr147fsTer22), that was found in compound heterozygous state in a patient with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; <a href="/entry/614739">614739</a>) by <a href="#2" class="mim-tip-reference" title="Lumish, H. S., Yang, Y., Xia, F., Wilson, A., Chung, W. K. <strong>The expanding MEGDEL phenotype: optic nerve atrophy, microcephaly, and myoclonic epilepsy in a child with SERAC1 mutations.</strong> JIMD Rep. 16: 75-79, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24997715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24997715</a>] [<a href="https://doi.org/10.1007/8904_2014_322" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24997715">Lumish et al. (2014)</a>, see <a href="#0001">614725.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24997715" 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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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-font">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
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<a id="Hartz2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Hartz, P. A.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 7/17/2012.
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<a id="Lumish2014" class="mim-anchor"></a>
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Lumish, H. S., Yang, Y., Xia, F., Wilson, A., Chung, W. K.
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<strong>The expanding MEGDEL phenotype: optic nerve atrophy, microcephaly, and myoclonic epilepsy in a child with SERAC1 mutations.</strong>
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JIMD Rep. 16: 75-79, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24997715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24997715</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24997715" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/8904_2014_322" target="_blank">Full Text</a>]
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<a id="Maas2017" class="mim-anchor"></a>
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<div class="">
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Maas, R. R., Iwanicka-Pronicka, K., Kalkan Ucar, S., Alhaddad, B., AlSayed, M., Al-Owain, M. A., Al-Zaidan, H. I., Balasubramaniam, S., Baric, I., Bubshait, D. K., Burlina, A., Christodoulou, J., and 46 others.
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<strong>Progressive deafness-dystonia due to SERAC1 mutations: a study of 67 cases.</strong>
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Ann. Neurol. 82: 1004-1015, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29205472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29205472</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29205472[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=29205472" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.25110" target="_blank">Full Text</a>]
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<a id="Rama Devi2018" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rama Devi, A. R., Lingappa, L.
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<strong>Novel mutations in SERAC1 gene in two Indian patients presenting with dystonia and intellectual disability.</strong>
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Europ. J. Med. Genet. 61: 100-103, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28778788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28778788</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28778788" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ejmg.2017.07.013" target="_blank">Full Text</a>]
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<a id="5" class="mim-anchor"></a>
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<a id="Roeben2018" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Roeben, B., Schule, R., Ruf, S., Bender, B., Alhaddad, B., Benkert, T., Meitinger, T., Reich, S., Bohringer, J., Langhans, C.-D., Vaz, F. M., Wortmann, S. B., Marquart, T., Haack, T. B., Krageloh-Mann, I., Schols, L., Synofzik, M.
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<strong>SERAC1 deficiency causes complicated HSP: evidence from a novel splice mutation in a large family.</strong>
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J. Med. Genet. 55: 39-47, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28916646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28916646</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28916646" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmedgenet-2017-104622" target="_blank">Full Text</a>]
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<a id="6" class="mim-anchor"></a>
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<a id="Tort2013" class="mim-anchor"></a>
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Tort, F., Garcia-Silva, M. T., Ferrer-Cortes, X., Navarro-Sastre, A., Garcia-Villoria, J., Coll, M. J., Vidal, E., Jimenez-Almazan, J., Dopazo, J., Briones, P., Elpeleg, O., Ribes, A.
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<strong>Exome sequencing identifies a new mutation in SERAC1 in a patient with 3-methylglutaconic aciduria.</strong>
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Molec. Genet. Metab. 110: 73-77, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23707711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23707711</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23707711" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ymgme.2013.04.021" target="_blank">Full Text</a>]
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<a id="Wortmann2012" class="mim-anchor"></a>
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Wortmann, S. B., Vaz, F. M., Gardeitchik, T., Vissers, L. E. L. M., Renkema, G. H., Schuurs-Hoeijmakers, J. H. M., Kulik, W., Lammens, M., Christin, C., Kluijtmans, L. A. J., Rodenburg, R. J., Nijtmans, L. G. J., and 22 others.
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<strong>Mutations in the phospholipid remodeling gene SERCA1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness.</strong>
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Nature Genet. 44: 797-802, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22683713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22683713</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22683713" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.2325" target="_blank">Full Text</a>]
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<a id="Wortmann2006" class="mim-anchor"></a>
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Wortmann, S., Rodenburg, R. J. T., Huizing, M., Loupatty, F. J., de Koning, T., Kluijtmans, L. A. J., Engelke, U., Wevers, R., Smeitink, J. A. M., Morava, E.
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<strong>Association of 3-methylglutaconic aciduria with sensori-neural deafness, encephalopathy, and Leigh-like syndrome (MEGDEL association) in four patients with a disorder of the oxidative phosphorylation.</strong>
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Molec. Genet. Metab. 88: 47-52, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16527507/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16527507</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16527507" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ymgme.2006.01.013" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 11/17/2021
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Cassandra L. Kniffin - updated : 02/19/2018<br>Cassandra L. Kniffin - updated : 01/26/2018<br>Cassandra L. Kniffin - updated : 3/18/2014<br>Cassandra L. Kniffin - updated : 7/24/2012
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Creation Date:
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Patricia A. Hartz : 7/17/2012
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carol : 11/17/2021
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carol : 02/23/2018<br>carol : 02/22/2018<br>ckniffin : 02/19/2018<br>carol : 01/31/2018<br>ckniffin : 01/26/2018<br>carol : 08/02/2017<br>carol : 03/18/2014<br>ckniffin : 3/18/2014<br>carol : 9/9/2013<br>terry : 7/30/2012<br>carol : 7/25/2012<br>ckniffin : 7/24/2012<br>mgross : 7/17/2012
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<strong>*</strong> 614725
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<h3>
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SERINE ACTIVE SITE-CONTAINING PROTEIN 1; SERAC1
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<strong>SNOMEDCT:</strong> 711409002;
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Cytogenetic location: 6q25.3
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|
Genomic coordinates <span class="small">(GRCh38)</span> : 6:158,109,519-158,168,262 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
6q25.3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
614739
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>SERAC1 functions in phosphatidylglycerol remodeling that is essential for mitochondrial function and intracellular cholesterol trafficking (Wortmann et al., 2012). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Wortmann et al. (2012) reported that the deduced SERAC1 protein has an N-terminal signal sequence and a C-terminal serine-lipase/esterase domain containing the consensus lipase motif GxSxG. Quantitative PCR analysis detected variable SERAC1 expression in all adult and fetal tissues examined, with highest expression in fetal skeletal muscle, followed by adult brain, fetal heart, and fetal kidney. Expression in fetal brain was much lower than that in adult brain. SERAC1 was detected in all specific adult brain regions examined, with highest expression in occipital cortex, followed by frontal cortex, cerebellum, and hippocampus. Western blot analysis of fractionated human fibroblasts and immunohistochemical analysis showed SERAC1 localization in both mitochondria and endoplasmic reticulum in a pattern consistent with enrichment in the mitochondria-associated membranes. Database analysis identified SERAC1 orthologs in all eukaryotes examined, with highest conservation in the lipase domain. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Wortmann et al. (2012) assayed control fibroblasts and fibroblasts from patients with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; 614739) due to SERAC1 mutations and transfected patient fibroblasts with wildtype SERAC1. The results showed that SERAC1 functions in the transacylation-acylation reaction that converts phosphatidylglycerol-34:1 to phosphatidylglycerol-36:1. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Wortmann et al. (2012) determined that the SERAC1 gene contains 17 exons and spans about 59 kb. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Hartz (2012) mapped the SERAC1 gene to chromosome 6q25.3 based on an alignment of the SERAC1 sequence (GenBank AK027823) with the genomic sequence (GRCh37).</p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>In 15 individuals from 13 families with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; 614739), which is also referred to as 3-methylglutaconic aciduria type VI (MGCA6), Wortmann et al. (2012) identified 14 different homozygous or compound heterozygous mutations in the SERAC1 gene (see, e.g., 614725.0001-614725.0005). The first 2 mutations were identified by exome sequencing and confirmed by Sanger sequencing. The patients had psychomotor retardation, spasticity and/or dystonia, deafness, and brain lesions on MRI. Laboratory studies showed increased serum lactate and alanine, urinary 3-MGA, mitochondrial oxidative phosphorylation defects, abnormal mitochondria, an abnormal phosphatidylglycerol and cardiolipin spectrum in fibroblasts, and abnormal accumulation of unesterified cholesterol within cells. </p><p>In a patient with MEGDEL, Tort et al. (2013) identified a homozygous truncating mutation in the SERAC1 gene (R68X; 614725.0006). The mutation was found by exome sequencing and segregated with the disorder in the family. </p><p>Among 67 patients with MEGDEL, including 39 previously unreported individuals, Maas et al. (2017) identified 41 SERAC1 sequence variants, including 20 novel variants. (Maas et al. (2017) used the acronym MEGDHEL to include the clinical feature of hepatopathy.) The mutations were located throughout the gene, with no hotspots, although there were several recurrent mutations, suggesting founder effects in certain populations. Most of the mutations were predicted to result in a loss of function, suggesting that missense mutations may be better tolerated. </p><p>In 2 unrelated Indian patients, born to consanguineous parents, with MEGDEL, Rama Devi and Lingappa (2018) identified homozygous mutations in the SERAC1 gene (614725.0008 and 614725.0009). The mutations were found by whole-exome sequencing. In 1 family, the parents were confirmed by Sanger sequencing to be carriers; in the other family, the parents refused to be sequenced. </p><p>In a Saudi Arabian boy with MEGDEL, Lumish et al. (2014) identified compound heterozygous mutations in the SERAC1 gene (614725.0001 and 614725.0010). The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. The father carried one of the mutations; the mother's status was not given. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>10 Selected Examples):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 3-@METHYLGLUTACONIC ACIDURIA WITH DEAFNESS, ENCEPHALOPATHY, AND LEIGH-LIKE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SERAC1, ARG148TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387907236,
|
|
|
|
|
|
gnomAD: rs387907236,
|
|
|
|
|
|
ClinVar: RCV000029218, RCV000414395
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 members of a consanguineous Turkish family with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; 614739), Wortmann et al. (2012) identified a homozygous 442C-T transition in the SERAC1 gene, resulting in an arg148-to-ter (R148X) substitution. The mutation was identified by exome sequencing and confirmed by Sanger sequencing, and was not found in 369 controls. The index patient had previously been reported as patient 3 by Wortmann et al. (2006). Clinical features included psychomotor retardation, recurrent infections in infancy, hypoglycemia, spasticity, dystonia, sensorineural deafness, brain atrophy, and lesions on brain imaging. Laboratory studies showed increased serum lactate and alanine, urinary 3-MGA, mitochondrial oxidative phosphorylation defects, abnormal mitochondria, an abnormal phosphatidylglycerol and cardiolipin spectrum in fibroblasts, and abnormal accumulation of unesterified cholesterol within cells. </p><p>In a Saudi Arabian patient with MEGDEL, Lumish et al. (2014) identified compound heterozygous mutations in the SERAC1 gene: R148X and a 1-bp deletion (c.438delC; 614725.0010) in the SERAC1 gene, predicted to result in a frameshift and premature termination (Thr147fsTer22). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The patient's father was shown to be a carrier of the c.438delC mutation. The c.438delC mutation was not present in the 1000 Genomes Project and EVS databases. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 3-@METHYLGLUTACONIC ACIDURIA WITH DEAFNESS, ENCEPHALOPATHY, AND LEIGH-LIKE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SERAC1, IVS13DS, G-C, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1131690799,
|
|
|
|
|
|
gnomAD: rs1131690799,
|
|
|
|
|
|
ClinVar: RCV000494708
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated patients with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; 614739), Wortmann et al. (2012) identified a homozygous G-to-C transversion in the donor splice site of exon 13 of the SERAC1 gene (1403+1G-C), resulting in the skipping of exon 13 and nonsense-mediated mRNA decay. One patient was born of consanguineous Pakistani parents and the other of unrelated Indian parents; haplotype analysis suggested a founder effect. The mutation was not found in 369 controls. The patients had psychomotor retardation, spasticity, dystonia, Leigh syndrome-like lesions on brain imaging, and increased urinary 3-MGA. Only 1 had hearing loss. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 3-@METHYLGLUTACONIC ACIDURIA WITH DEAFNESS, ENCEPHALOPATHY, AND LEIGH-LIKE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SERAC1, 4-BP DEL, 1167TCAG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs772296795,
|
|
|
|
|
|
gnomAD: rs772296795,
|
|
|
|
|
|
ClinVar: RCV000029220
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Turkish girl, born of consanguineous parents, with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; 614739), Wortmann et al. (2012) identified a homozygous 4-bp deletion (1167delTCAG) in a canonical splice site of the SERAC1 gene, resulting in the skipping of exon 12 and nonsense-mediated mRNA decay. The mutation was not found in 369 controls. The patient, who was originally reported as patient 1 by Wortmann et al. (2006), had recurrent infections, failure to thrive, mental retardation, spasticity and extrapyramidal symptoms, deafness, hypoglycemia, increased serum lactate, abnormal lesions on brain imaging, and oxidative phosphorylation defects. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 3-@METHYLGLUTACONIC ACIDURIA WITH DEAFNESS, ENCEPHALOPATHY, AND LEIGH-LIKE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SERAC1, 3-BP DEL, 1435CTT
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1199625391,
|
|
|
|
|
|
gnomAD: rs1199625391,
|
|
|
|
|
|
ClinVar: RCV000029221
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Turkish girl, born of consanguineous parents, with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; 614739), Wortmann et al. (2012) identified a homozygous 3-bp deletion (1435delCTT) in the SERAC1 gene, resulting in an in-frame deletion of an amino acid in the highly conserved lipase domain. The patient was originally reported as patient 4 by Wortmann et al. (2006). The mutation was not found in 369 controls. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 3-@METHYLGLUTACONIC ACIDURIA WITH DEAFNESS, ENCEPHALOPATHY, AND LEIGH-LIKE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SERAC1, 2-BP DUP, 1627TC
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs767780913,
|
|
|
|
|
|
gnomAD: rs767780913,
|
|
|
|
|
|
ClinVar: RCV000029222, RCV000195622
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Dutch girl with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; 614739), Wortmann et al. (2012) identified a homozygous 2-bp duplication (1627dupTC) in the SERAC1 gene, resulting in a frameshift and premature termination (Val544LeufsTer43). The patient was originally reported as patient 2 by Wortmann et al. (2006). The mutation was not found in 369 controls. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 3-@METHYLGLUTACONIC ACIDURIA WITH DEAFNESS, ENCEPHALOPATHY, AND LEIGH-LIKE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SERAC1, ARG68TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs529232938,
|
|
|
|
|
|
gnomAD: rs529232938,
|
|
|
|
|
|
ClinVar: RCV000106307
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; 614739), Tort et al. (2013) identified a homozygous c.202C-T transition in the SERAC1 gene, resulting in an arg68-to-ter (R68X) substitution. Western blot of patient cells showed no detectable SERAC1 protein. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 3-@METHYLGLUTACONIC ACIDURIA WITH DEAFNESS, ENCEPHALOPATHY, AND LEIGH-LIKE SYNDROME, MILD VARIANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SERAC1, IVS2DS, T-C, +6
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1554265452,
|
|
|
|
|
|
|
|
ClinVar: RCV000578380
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
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<p>In 6 members of a large consanguineous Iraqi family with a mild variant of 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; 614739), Roeben et al. (2018) identified a homozygous T-to-C transition (c.91+6T-C, NM_032861.3) close to the canonical splice donor of exon 2 in the SERAC1 gene, which is the first coding exon in the transcript. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP (build 142), 1000 Genomes Project, or ExAC (February 2016) databases, or in 8,000 in-house exomes. Analysis of patient cells showed 2 shortened mutant SERAC1 transcripts lacking exon 2 and exons 2 and 3, respectively. There was no suggestion of mRNA decay, but Western blot analysis detected no full-length SERAC1 protein. Patient cells showed impaired phosphatidylglycerol remodeling, although the changes were milder than that observed in other patients with MEGDEL. Correspondingly, the patients presented with juvenile-onset progressive spastic paraplegia and mild cognitive impairment, although none had deafness. The findings expanded the phenotypic spectrum associated with SERAC1 mutations. </p>
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<strong>.0008 3-@METHYLGLUTACONIC ACIDURIA WITH DEAFNESS, ENCEPHALOPATHY, AND LEIGH-LIKE SYNDROME</strong>
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<span class="mim-text-font">
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SERAC1, 4-BP DUP, 1643ATCT
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<br />
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SNP: rs761964407,
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gnomAD: rs761964407,
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ClinVar: RCV000494711
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<p>In an Indian patient, born to consanguineous parents, with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; 614739), Rama Devi and Lingappa (2018) identified homozygosity for a 4-bp duplication (c.1643_1646dupATCT, NM_032861.3) in exon 15 of the SERAC1 gene, predicted to result in a frameshift and premature termination (Leu550fsTer19). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The mutation was not present in the 1000 Genomes Project database and was present in the ExAC database at a minor allele frequency of 0.02%. The patient had a history of neonatal hepatopathy and metabolic acidosis, developmental delay, and dystonia. Urine organic acid analysis in the patient showed elevations of 3-methylglutaconic and 3-methylglutaric acids. </p>
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<span class="mim-font">
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<strong>.0009 3-@METHYLGLUTACONIC ACIDURIA WITH DEAFNESS, ENCEPHALOPATHY, AND LEIGH-LIKE SYNDROME</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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SERAC1, GLY526GLU
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<br />
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SNP: rs1554261079,
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ClinVar: RCV000515616
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<p>In an 11-year-old Indian patient, born of consanguineous parents, with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; 614739), Rama Devi and Lingappa (2018) identified homozygosity for a c.1709G-A transition (c.1709G-A, NM_032861.3) in exon 15 of the SERAC1 gene, resulting in a gly526-to-glu (G526E) substitution. The mutation was identified by whole-exome sequencing. The mutation was not present in the 1000 Genomes Project and ExAC databases. The patient had a history of developmental regression, ataxia, jaundice, and basal ganglia abnormalities on MRI. Urine organic acid analysis in the patient showed mild elevations of 3-methylglutaconic and 3-methylglutaric acids. </p>
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<span class="mim-font">
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<strong>.0010 3-@METHYLGLUTACONIC ACIDURIA WITH DEAFNESS, ENCEPHALOPATHY, AND LEIGH-LIKE SYNDROME</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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SERAC1, 1-BP DEL, 438C
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<br />
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SNP: rs1583595091,
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ClinVar: RCV000850598
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<span class="mim-text-font">
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<p>For description of the 1-bp deletion (c.438delC) in the SERAC1 gene, predicted to result in a frameshift and premature termination (Thr147fsTer22), that was found in compound heterozygous state in a patient with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL; 614739) by Lumish et al. (2014), see 614725.0001. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<ol>
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<li>
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<p class="mim-text-font">
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Hartz, P. A.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 7/17/2012.
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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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Lumish, H. S., Yang, Y., Xia, F., Wilson, A., Chung, W. K.
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<strong>The expanding MEGDEL phenotype: optic nerve atrophy, microcephaly, and myoclonic epilepsy in a child with SERAC1 mutations.</strong>
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JIMD Rep. 16: 75-79, 2014.
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[PubMed: 24997715]
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[Full Text: https://doi.org/10.1007/8904_2014_322]
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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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Maas, R. R., Iwanicka-Pronicka, K., Kalkan Ucar, S., Alhaddad, B., AlSayed, M., Al-Owain, M. A., Al-Zaidan, H. I., Balasubramaniam, S., Baric, I., Bubshait, D. K., Burlina, A., Christodoulou, J., and 46 others.
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<strong>Progressive deafness-dystonia due to SERAC1 mutations: a study of 67 cases.</strong>
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Ann. Neurol. 82: 1004-1015, 2017.
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[PubMed: 29205472]
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[Full Text: https://doi.org/10.1002/ana.25110]
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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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Rama Devi, A. R., Lingappa, L.
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<strong>Novel mutations in SERAC1 gene in two Indian patients presenting with dystonia and intellectual disability.</strong>
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Europ. J. Med. Genet. 61: 100-103, 2018.
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[PubMed: 28778788]
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[Full Text: https://doi.org/10.1016/j.ejmg.2017.07.013]
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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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Roeben, B., Schule, R., Ruf, S., Bender, B., Alhaddad, B., Benkert, T., Meitinger, T., Reich, S., Bohringer, J., Langhans, C.-D., Vaz, F. M., Wortmann, S. B., Marquart, T., Haack, T. B., Krageloh-Mann, I., Schols, L., Synofzik, M.
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<strong>SERAC1 deficiency causes complicated HSP: evidence from a novel splice mutation in a large family.</strong>
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J. Med. Genet. 55: 39-47, 2018.
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[PubMed: 28916646]
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[Full Text: https://doi.org/10.1136/jmedgenet-2017-104622]
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</li>
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<li>
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<p class="mim-text-font">
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Tort, F., Garcia-Silva, M. T., Ferrer-Cortes, X., Navarro-Sastre, A., Garcia-Villoria, J., Coll, M. J., Vidal, E., Jimenez-Almazan, J., Dopazo, J., Briones, P., Elpeleg, O., Ribes, A.
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<strong>Exome sequencing identifies a new mutation in SERAC1 in a patient with 3-methylglutaconic aciduria.</strong>
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Molec. Genet. Metab. 110: 73-77, 2013.
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[PubMed: 23707711]
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[Full Text: https://doi.org/10.1016/j.ymgme.2013.04.021]
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<p class="mim-text-font">
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Wortmann, S. B., Vaz, F. M., Gardeitchik, T., Vissers, L. E. L. M., Renkema, G. H., Schuurs-Hoeijmakers, J. H. M., Kulik, W., Lammens, M., Christin, C., Kluijtmans, L. A. J., Rodenburg, R. J., Nijtmans, L. G. J., and 22 others.
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<strong>Mutations in the phospholipid remodeling gene SERCA1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness.</strong>
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Nature Genet. 44: 797-802, 2012.
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[PubMed: 22683713]
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[Full Text: https://doi.org/10.1038/ng.2325]
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<p class="mim-text-font">
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Wortmann, S., Rodenburg, R. J. T., Huizing, M., Loupatty, F. J., de Koning, T., Kluijtmans, L. A. J., Engelke, U., Wevers, R., Smeitink, J. A. M., Morava, E.
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<strong>Association of 3-methylglutaconic aciduria with sensori-neural deafness, encephalopathy, and Leigh-like syndrome (MEGDEL association) in four patients with a disorder of the oxidative phosphorylation.</strong>
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Molec. Genet. Metab. 88: 47-52, 2006.
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[PubMed: 16527507]
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[Full Text: https://doi.org/10.1016/j.ymgme.2006.01.013]
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Hilary J. Vernon - updated : 11/17/2021<br>Cassandra L. Kniffin - updated : 02/19/2018<br>Cassandra L. Kniffin - updated : 01/26/2018<br>Cassandra L. Kniffin - updated : 3/18/2014<br>Cassandra L. Kniffin - updated : 7/24/2012
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