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Entry
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- *611006 - IRON-SULFUR CLUSTER ASSEMBLY 1; ISCA1
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- OMIM
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<p>
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<span class="h4">*611006</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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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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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/611006">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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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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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 id="mimFloatingLinksMenu">
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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="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=ENSG00000135070;t=ENST00000375991" 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=81689" 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=611006" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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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=ENSG00000135070;t=ENST00000375991" 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_030940" 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_030940" 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=611006" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=17091&isoform_id=17091_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/ISCA1" 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/12584843,12803679,18025262,21740005,47940458,52426768,74761270,119583116,119583117,193786263,194382184" 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/Q9BUE6" 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=81689" 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=ENSG00000135070;t=ENST00000375991" 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=ISCA1" 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=ISCA1" 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+81689" 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/ISCA1" 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:81689" 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/81689" 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=chr9&hgg_gene=ENST00000375991.9&hgg_start=86264546&hgg_end=86282538&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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=611006[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 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=611006[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/ENSG00000135070" 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=ISCA1" 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=ISCA1" 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=ISCA1" 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=ISCA1&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/PA162392301" 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:28660" 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/FBgn0026666.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/search?q=MGI:1916296 MGI:3574096" 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/ISCA1#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/batch/summary?idType=MGI&ids=MGI:1916296 MGI:3574096" 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/81689/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=81689" 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=WBGene00012666;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-050626-94" 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=ISCA1&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> 1279890001<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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611006
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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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IRON-SULFUR CLUSTER ASSEMBLY 1; ISCA1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
IRON-SULFUR CLUSTER ASSEMBLY 1, S. CEREVISIAE, HOMOLOG OF<br />
|
|
HESB-LIKE DOMAIN-CONTAINING 2; HBLD2<br />
|
|
HISCA
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=ISCA1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ISCA1</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/9/280?start=-3&limit=10&highlight=280">9q21.33</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr9:86264546-86282538&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'})">9:86,264,546-86,282,538</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">
|
|
<a href="/geneMap/9/280?start=-3&limit=10&highlight=280">
|
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9q21.33
|
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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">
|
|
Multiple mitochondrial dysfunctions syndrome 5
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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/617613"> 617613 </a>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal 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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|
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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">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/611006" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/611006" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<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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|
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<span class="mim-font">
|
|
<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.">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</span>
|
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</h4>
|
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<div>
|
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<a id="description" class="mim-anchor"></a>
|
|
<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<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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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>ISCA1, like IBA57 (<a href="/entry/615316">615316</a>) and ISCA2 (<a href="/entry/615317">615317</a>), is part of the iron-sulfur cluster (ISC) assembly machinery in mitochondria. These 3 proteins function late in the biosynthetic pathway of mitochondrial 4Fe-4S proteins (<a href="#3" class="mim-tip-reference" title="Sheftel, A. D., Wilbrecht, C., Stehling, O., Niggemeyer, B., Elsasser, H.-P., Muhlenhoff, U., Lill, R. <strong>The human mitochondrial ISCA1, ISCA2, and IBA57 proteins are required for [4Fe-4S] protein maturation.</strong> Molec. Biol. Cell 23: 1157-1166, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22323289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22323289</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22323289[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/10.1091/mbc.E11-09-0772" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22323289">Sheftel et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22323289" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By immunoscreening a human brain cDNA expression library with serum from a patient with Sjogren syndrome (<a href="/entry/270150">270150</a>), followed by database analysis, <a href="#1" class="mim-tip-reference" title="Cozar-Castellano, I., del Valle Machargo, M., Trujillo, E., Arteaga, M. F., Gonzalez, T., Martin-Vasallo, P., Avila, J. <strong>hIscA: a protein implicated in the biogenesis of iron-sulfur clusters.</strong> Biochim. Biophys. Acta 1700: 179-188, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15262227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15262227</a>] [<a href="https://doi.org/10.1016/j.bbapap.2004.05.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15262227">Cozar-Castellano et al. (2004)</a> cloned ISCA1, which they called HBLD2. The deduced 129-amino acid protein has a predicted molecular mass of 15.5 kD and shares 97% amino acid identity with its rat ortholog. ISCA1 has a conserved C-terminal HESB domain, and the 5-prime untranslated region contains an SP1 binding site. Northern blot analysis detected a 2.8-kb transcript with high expression in cerebellum and kidney and lower expression in heart and liver. Immunocytochemistry studies localized ISCA1 to mitochondria when expressed in rat neuroblastoma cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15262227" 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>Using a computational screen to identify human and mouse genes encoding mitochondrial proteins involved in heme biosynthesis, <a href="#2" class="mim-tip-reference" title="Nilsson, R., Schultz, I. J., Pierce, E. L., Soltis, K. A., Naranuntarat, A., Ward, D. M., Baughman, J. M., Paradkar, P. N., Kingsley, P. D., Culotta, V. C., Kaplan, J., Palis, J., Paw, B. H., Mootha, V. K. <strong>Discovery of genes essential for heme biosynthesis through large-scale gene expression analysis.</strong> Cell Metab. 10: 119-130, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19656490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19656490</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19656490[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/10.1016/j.cmet.2009.06.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19656490">Nilsson et al. (2009)</a> identified ISCA1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19656490" 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>Using cell fractionation, immunoblot analysis, and confocal microscopy, <a href="#3" class="mim-tip-reference" title="Sheftel, A. D., Wilbrecht, C., Stehling, O., Niggemeyer, B., Elsasser, H.-P., Muhlenhoff, U., Lill, R. <strong>The human mitochondrial ISCA1, ISCA2, and IBA57 proteins are required for [4Fe-4S] protein maturation.</strong> Molec. Biol. Cell 23: 1157-1166, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22323289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22323289</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22323289[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/10.1091/mbc.E11-09-0772" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22323289">Sheftel et al. (2012)</a> demonstrated mitochondrial localization of human ISCA1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22323289" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#1" class="mim-tip-reference" title="Cozar-Castellano, I., del Valle Machargo, M., Trujillo, E., Arteaga, M. F., Gonzalez, T., Martin-Vasallo, P., Avila, J. <strong>hIscA: a protein implicated in the biogenesis of iron-sulfur clusters.</strong> Biochim. Biophys. Acta 1700: 179-188, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15262227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15262227</a>] [<a href="https://doi.org/10.1016/j.bbapap.2004.05.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15262227">Cozar-Castellano et al. (2004)</a> showed that expression of ISCA1 functionally complemented an Isa1-null mutant yeast strain, suggesting that ISCA1 likely plays a role in biogenesis of mitochondrial iron-sulfur clusters. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15262227" 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>Using a yeast 2-hybrid screen of a human kidney cDNA library to identify IOP1 (NARFL; <a href="/entry/611118">611118</a>)-interacting proteins, <a href="#5" class="mim-tip-reference" title="Song, D., Tu, Z., Lee, F. S. <strong>Human ISCA1 interacts with IOP1/NARFL and functions in both cytosolic and mitochondrial iron-sulfur protein biogenesis.</strong> J. Biol. Chem. 284: 35297-35307, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19864422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19864422</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19864422[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/10.1074/jbc.M109.040014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19864422">Song et al. (2009)</a> identified ISCA1. Immunoprecipitation analysis showed that the interaction required 3 conserved cysteines in ISCA1 predicted to be involved in binding iron/sulfur clusters. Western blot analysis revealed mitochondrial expression of ISCA1, as well as reduced cytosolic expression. Small interfering RNA-mediated knockdown of ISCA1 in HeLa cells resulted in decreased activity of 2 mitochondrial iron-sulfur enzymes, succinate dehydrogenase (see <a href="/entry/600857">600857</a>) and aconitase (ACO2; <a href="/entry/100850">100850</a>), as well the cytosolic iron-sulfur enzyme aconitase (ACO1; <a href="/entry/100880">100880</a>). <a href="#5" class="mim-tip-reference" title="Song, D., Tu, Z., Lee, F. S. <strong>Human ISCA1 interacts with IOP1/NARFL and functions in both cytosolic and mitochondrial iron-sulfur protein biogenesis.</strong> J. Biol. Chem. 284: 35297-35307, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19864422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19864422</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19864422[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/10.1074/jbc.M109.040014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19864422">Song et al. (2009)</a> proposed that ISCA1 is important in both mitochondrial and cytosolic iron-sulfur biogenesis and that the cytosolic activity is affected by its interaction with IOP1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19864422" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Sheftel, A. D., Wilbrecht, C., Stehling, O., Niggemeyer, B., Elsasser, H.-P., Muhlenhoff, U., Lill, R. <strong>The human mitochondrial ISCA1, ISCA2, and IBA57 proteins are required for [4Fe-4S] protein maturation.</strong> Molec. Biol. Cell 23: 1157-1166, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22323289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22323289</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22323289[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/10.1091/mbc.E11-09-0772" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22323289">Sheftel et al. (2012)</a> used RNA interference to deplete HeLa cells of ISCA1, ISCA2, and IBA57 and observed swollen mitochondria devoid of cristae membranes. Depletion of these proteins also resulted in diminished activities of mitochondrial 4Fe-4S proteins, including aconitase, respiratory complex I (see <a href="/entry/602985">602985</a>), and lipoic acid synthase (LIAS; <a href="/entry/607031">607031</a>). In contrast, cellular heme content and mitochondrial 2Fe-2S ferrochelatase (FECH; <a href="/entry/612386">612386</a>) were unaffected. <a href="#3" class="mim-tip-reference" title="Sheftel, A. D., Wilbrecht, C., Stehling, O., Niggemeyer, B., Elsasser, H.-P., Muhlenhoff, U., Lill, R. <strong>The human mitochondrial ISCA1, ISCA2, and IBA57 proteins are required for [4Fe-4S] protein maturation.</strong> Molec. Biol. Cell 23: 1157-1166, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22323289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22323289</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22323289[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/10.1091/mbc.E11-09-0772" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22323289">Sheftel et al. (2012)</a> proposed that ISCA1, ISCA2, and IBA57 are specifically involved in the maturation of mitochondrial 4Fe-4S proteins functioning late in the ISC assembly pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22323289" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#1" class="mim-tip-reference" title="Cozar-Castellano, I., del Valle Machargo, M., Trujillo, E., Arteaga, M. F., Gonzalez, T., Martin-Vasallo, P., Avila, J. <strong>hIscA: a protein implicated in the biogenesis of iron-sulfur clusters.</strong> Biochim. Biophys. Acta 1700: 179-188, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15262227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15262227</a>] [<a href="https://doi.org/10.1016/j.bbapap.2004.05.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15262227">Cozar-Castellano et al. (2004)</a> determined that the ISCA1 gene contains 4 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15262227" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By genomic sequence analysis, <a href="#1" class="mim-tip-reference" title="Cozar-Castellano, I., del Valle Machargo, M., Trujillo, E., Arteaga, M. F., Gonzalez, T., Martin-Vasallo, P., Avila, J. <strong>hIscA: a protein implicated in the biogenesis of iron-sulfur clusters.</strong> Biochim. Biophys. Acta 1700: 179-188, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15262227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15262227</a>] [<a href="https://doi.org/10.1016/j.bbapap.2004.05.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15262227">Cozar-Castellano et al. (2004)</a> mapped the ISCA1 gene to chromosome 9q21.2-q22.1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15262227" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 unrelated, deceased probands of Indian descent with multiple mitochondrial dysfunctions syndrome-5 (MMDS5; <a href="/entry/617613">617613</a>), <a href="#4" class="mim-tip-reference" title="Shukla, A., Hebbar, M., Srivastava, A., Kadavigere, R., Upadhyai, P., Kanthi, A., Brandau, O., Bielas, S., Girisha, K. M. <strong>Homozygous p.(Glu8Lys) variant in ISCA1 is associated with a multiple mitochondrial dysfunctions syndrome.</strong> J. Hum. Genet. 62: 723-727, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28356563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28356563</a>] [<a href="https://doi.org/10.1038/jhg.2017.35" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28356563">Shukla et al. (2017)</a> identified a homozygous missense mutation in the ISCA1 gene (E87K; <a href="#0001">611006.0001</a>). Molecular modeling predicted that the mutation would lead to destabilization of the protein. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Haplotype analysis suggested a founder effect. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28356563" 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 an Italian boy with MMDS5, <a href="#6" class="mim-tip-reference" title="Torraco, A., Stehling, O., Stumpfig, C., Rosser, R., De Rasmo, D., Fiermonte, G., Verrigni, D., Rizza, T., Vozza, A., Di Nottia, M., Diodato, D., Martinelli, D., Piemonte, F., Dionisi-Vici, C., Bertini, E., Lill, R., Carrozzo, R. <strong>ISCA1 mutation in a patient with infantile-onset leukodystrophy causes defects in mitochondrial [4Fe-4S] proteins.</strong> Hum. Molec. Genet. 27: 2739-2754, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29767723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29767723</a>] [<a href="https://doi.org/10.1093/hmg/ddy183" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29767723">Torraco et al. (2018)</a> identified a homozygous missense mutation (V10G; <a href="#0002">611006.0002</a>) in the ISCA1 gene. The mutation was detected by next-generation sequencing of a mitochondrial-targeted gene panel and confirmed by Sanger sequencing. Both parents and an unaffected sib were heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29767723" 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="#2" class="mim-tip-reference" title="Nilsson, R., Schultz, I. J., Pierce, E. L., Soltis, K. A., Naranuntarat, A., Ward, D. M., Baughman, J. M., Paradkar, P. N., Kingsley, P. D., Culotta, V. C., Kaplan, J., Palis, J., Paw, B. H., Mootha, V. K. <strong>Discovery of genes essential for heme biosynthesis through large-scale gene expression analysis.</strong> Cell Metab. 10: 119-130, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19656490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19656490</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19656490[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/10.1016/j.cmet.2009.06.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19656490">Nilsson et al. (2009)</a> found that targeted knockdown of Isca1 in zebrafish resulted in profound anemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19656490" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=611006[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 5</strong>
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ISCA1, GLU87LYS (<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=SCV000328646" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ClinVar\', \'domain\': \'ncbi.nlm.nih.gov\'})">SCV000328646</a>)
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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> rs776679653 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs776679653;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/rs776679653?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=rs776679653" 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=rs776679653" 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=RCV000497255 OR RCV000508655" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000497255, RCV000508655" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000497255...</a>
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<p>In 2 unrelated probands of Indian descent with multiple mitochondrial dysfunctions syndrome-5 (MMDS5; <a href="/entry/617613">617613</a>), <a href="#4" class="mim-tip-reference" title="Shukla, A., Hebbar, M., Srivastava, A., Kadavigere, R., Upadhyai, P., Kanthi, A., Brandau, O., Bielas, S., Girisha, K. M. <strong>Homozygous p.(Glu8Lys) variant in ISCA1 is associated with a multiple mitochondrial dysfunctions syndrome.</strong> J. Hum. Genet. 62: 723-727, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28356563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28356563</a>] [<a href="https://doi.org/10.1038/jhg.2017.35" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28356563">Shukla et al. (2017)</a> identified a homozygous c.259G-A transition (c.259G-A, NM_030940.3) in exon 4 of the ISCA1 gene, resulting in a glu87-to-lys (E87K) substitution at a conserved residue in the Fe-S biogenesis domain. Molecular modeling predicted that the mutation would lead to destabilization of the protein. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The mutation was not found in homozygous state in the 1000 Genomes Project or the Exome Variant Server databases or in an in-house exome database of 139 individuals from the same population; however, the variant was found at very low frequencies in heterozygous state in the ExAC and gnomAD databases. Both probands had a similarly affected sib, although biologic material was not available from the sibs. All of the children were deceased at the time of the report. Haplotype analysis suggested a founder effect. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28356563" 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>.0002 MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 5</strong>
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ISCA1, VAL10GLY
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1587823007 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1587823007;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=rs1587823007" 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=rs1587823007" 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=RCV000857321" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000857321" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000857321</a>
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<p>In an Italian boy with multiple mitochondrial dysfunctions syndrome-5 (MMDS5; <a href="/entry/617613">617613</a>), <a href="#6" class="mim-tip-reference" title="Torraco, A., Stehling, O., Stumpfig, C., Rosser, R., De Rasmo, D., Fiermonte, G., Verrigni, D., Rizza, T., Vozza, A., Di Nottia, M., Diodato, D., Martinelli, D., Piemonte, F., Dionisi-Vici, C., Bertini, E., Lill, R., Carrozzo, R. <strong>ISCA1 mutation in a patient with infantile-onset leukodystrophy causes defects in mitochondrial [4Fe-4S] proteins.</strong> Hum. Molec. Genet. 27: 2739-2754, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29767723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29767723</a>] [<a href="https://doi.org/10.1093/hmg/ddy183" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29767723">Torraco et al. (2018)</a> identified a homozygous c.29T-G transversion (c.29T-G, NM_030940.3) in exon 1 of the ISCA1 gene, resulting in a val10-to-gly (V10G) substitution at a moderately conserved residue predicted to be located in the presequence part of the protein. The mutation was detected by next-generation sequencing of a mitochondrial-targeted gene panel and confirmed by Sanger sequencing. The parents were heterozygous for the mutation. An older sib died at 1 year of age with clinical features of MMDS5, but molecular testing was not performed. The mutation was not present in the dbSNP, ExAC, and EVS databases. Postmortem brain and muscle tissue from the patient had multiple defects of respiratory chain complex activities. Studies in patient fibroblasts showed reduction of ISCA1 protein content, reduction of the [4Fe-4S] cluster-containing proteins NDUFS1 (<a href="/entry/157655">157655</a>) and SDHB (<a href="/entry/185470">185470</a>), and reduction in ATP synthesis with succinate, malate, and pyruvate as substrates. Functional analysis of the ISCA1 protein containing the V10G mutation in HeLa cells showed decreased mitochondrial ISCA1 protein import, stability, and biologic function in the mitochondrial matrix. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29767723" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
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<a id="Cozar-Castellano2004" class="mim-anchor"></a>
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Cozar-Castellano, I., del Valle Machargo, M., Trujillo, E., Arteaga, M. F., Gonzalez, T., Martin-Vasallo, P., Avila, J.
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<strong>hIscA: a protein implicated in the biogenesis of iron-sulfur clusters.</strong>
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Biochim. Biophys. Acta 1700: 179-188, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15262227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15262227</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15262227" 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.bbapap.2004.05.004" target="_blank">Full Text</a>]
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<a id="Nilsson2009" class="mim-anchor"></a>
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Nilsson, R., Schultz, I. J., Pierce, E. L., Soltis, K. A., Naranuntarat, A., Ward, D. M., Baughman, J. M., Paradkar, P. N., Kingsley, P. D., Culotta, V. C., Kaplan, J., Palis, J., Paw, B. H., Mootha, V. K.
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<strong>Discovery of genes essential for heme biosynthesis through large-scale gene expression analysis.</strong>
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Cell Metab. 10: 119-130, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19656490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19656490</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19656490[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=19656490" 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.cmet.2009.06.012" target="_blank">Full Text</a>]
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<a id="Sheftel2012" class="mim-anchor"></a>
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Sheftel, A. D., Wilbrecht, C., Stehling, O., Niggemeyer, B., Elsasser, H.-P., Muhlenhoff, U., Lill, R.
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<strong>The human mitochondrial ISCA1, ISCA2, and IBA57 proteins are required for [4Fe-4S] protein maturation.</strong>
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Molec. Biol. Cell 23: 1157-1166, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22323289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22323289</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22323289[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=22323289" 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/10.1091/mbc.E11-09-0772" target="_blank">Full Text</a>]
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<a id="Shukla2017" class="mim-anchor"></a>
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Shukla, A., Hebbar, M., Srivastava, A., Kadavigere, R., Upadhyai, P., Kanthi, A., Brandau, O., Bielas, S., Girisha, K. M.
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<strong>Homozygous p.(Glu8Lys) variant in ISCA1 is associated with a multiple mitochondrial dysfunctions syndrome.</strong>
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J. Hum. Genet. 62: 723-727, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28356563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28356563</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28356563" 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/jhg.2017.35" target="_blank">Full Text</a>]
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<a id="Song2009" class="mim-anchor"></a>
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Song, D., Tu, Z., Lee, F. S.
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<strong>Human ISCA1 interacts with IOP1/NARFL and functions in both cytosolic and mitochondrial iron-sulfur protein biogenesis.</strong>
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J. Biol. Chem. 284: 35297-35307, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19864422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19864422</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19864422[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=19864422" 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/10.1074/jbc.M109.040014" target="_blank">Full Text</a>]
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<a id="Torraco2018" class="mim-anchor"></a>
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Torraco, A., Stehling, O., Stumpfig, C., Rosser, R., De Rasmo, D., Fiermonte, G., Verrigni, D., Rizza, T., Vozza, A., Di Nottia, M., Diodato, D., Martinelli, D., Piemonte, F., Dionisi-Vici, C., Bertini, E., Lill, R., Carrozzo, R.
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<strong>ISCA1 mutation in a patient with infantile-onset leukodystrophy causes defects in mitochondrial [4Fe-4S] proteins.</strong>
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Hum. Molec. Genet. 27: 2739-2754, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29767723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29767723</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29767723" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddy183" target="_blank">Full Text</a>]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 07/08/2020
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Cassandra L. Kniffin - updated : 08/09/2017<br>Paul J. Converse - updated : 8/20/2013<br>Paul J. Converse - updated : 7/18/2013
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Dorothy S. Reilly : 5/9/2007
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carol : 07/08/2020
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<span class="mim-text-font">
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alopez : 08/28/2019<br>carol : 08/10/2017<br>ckniffin : 08/09/2017<br>mgross : 08/20/2013<br>mgross : 8/20/2013<br>mgross : 7/18/2013<br>mgross : 7/18/2013<br>mgross : 7/18/2013<br>wwang : 5/9/2007
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<span class="mim-font">
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<strong>*</strong> 611006
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IRON-SULFUR CLUSTER ASSEMBLY 1; ISCA1
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<span class="mim-font">
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IRON-SULFUR CLUSTER ASSEMBLY 1, S. CEREVISIAE, HOMOLOG OF<br />
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HESB-LIKE DOMAIN-CONTAINING 2; HBLD2<br />
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HISCA
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: ISCA1</em></strong>
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<strong>SNOMEDCT:</strong> 1279890001;
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<strong>
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Cytogenetic location: 9q21.33
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Genomic coordinates <span class="small">(GRCh38)</span> : 9:86,264,546-86,282,538 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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</th>
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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9q21.33
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<span class="mim-font">
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Multiple mitochondrial dysfunctions syndrome 5
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<span class="mim-font">
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617613
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<span class="mim-font">
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Autosomal recessive
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<span class="mim-font">
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<strong>Description</strong>
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<span class="mim-text-font">
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<p>ISCA1, like IBA57 (615316) and ISCA2 (615317), is part of the iron-sulfur cluster (ISC) assembly machinery in mitochondria. These 3 proteins function late in the biosynthetic pathway of mitochondrial 4Fe-4S proteins (Sheftel et al., 2012). </p>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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<span class="mim-text-font">
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<p>By immunoscreening a human brain cDNA expression library with serum from a patient with Sjogren syndrome (270150), followed by database analysis, Cozar-Castellano et al. (2004) cloned ISCA1, which they called HBLD2. The deduced 129-amino acid protein has a predicted molecular mass of 15.5 kD and shares 97% amino acid identity with its rat ortholog. ISCA1 has a conserved C-terminal HESB domain, and the 5-prime untranslated region contains an SP1 binding site. Northern blot analysis detected a 2.8-kb transcript with high expression in cerebellum and kidney and lower expression in heart and liver. Immunocytochemistry studies localized ISCA1 to mitochondria when expressed in rat neuroblastoma cells. </p><p>Using a computational screen to identify human and mouse genes encoding mitochondrial proteins involved in heme biosynthesis, Nilsson et al. (2009) identified ISCA1. </p><p>Using cell fractionation, immunoblot analysis, and confocal microscopy, Sheftel et al. (2012) demonstrated mitochondrial localization of human ISCA1. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Cozar-Castellano et al. (2004) showed that expression of ISCA1 functionally complemented an Isa1-null mutant yeast strain, suggesting that ISCA1 likely plays a role in biogenesis of mitochondrial iron-sulfur clusters. </p><p>Using a yeast 2-hybrid screen of a human kidney cDNA library to identify IOP1 (NARFL; 611118)-interacting proteins, Song et al. (2009) identified ISCA1. Immunoprecipitation analysis showed that the interaction required 3 conserved cysteines in ISCA1 predicted to be involved in binding iron/sulfur clusters. Western blot analysis revealed mitochondrial expression of ISCA1, as well as reduced cytosolic expression. Small interfering RNA-mediated knockdown of ISCA1 in HeLa cells resulted in decreased activity of 2 mitochondrial iron-sulfur enzymes, succinate dehydrogenase (see 600857) and aconitase (ACO2; 100850), as well the cytosolic iron-sulfur enzyme aconitase (ACO1; 100880). Song et al. (2009) proposed that ISCA1 is important in both mitochondrial and cytosolic iron-sulfur biogenesis and that the cytosolic activity is affected by its interaction with IOP1. </p><p>Sheftel et al. (2012) used RNA interference to deplete HeLa cells of ISCA1, ISCA2, and IBA57 and observed swollen mitochondria devoid of cristae membranes. Depletion of these proteins also resulted in diminished activities of mitochondrial 4Fe-4S proteins, including aconitase, respiratory complex I (see 602985), and lipoic acid synthase (LIAS; 607031). In contrast, cellular heme content and mitochondrial 2Fe-2S ferrochelatase (FECH; 612386) were unaffected. Sheftel et al. (2012) proposed that ISCA1, ISCA2, and IBA57 are specifically involved in the maturation of mitochondrial 4Fe-4S proteins functioning late in the ISC assembly pathway. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Cozar-Castellano et al. (2004) determined that the ISCA1 gene contains 4 exons. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By genomic sequence analysis, Cozar-Castellano et al. (2004) mapped the ISCA1 gene to chromosome 9q21.2-q22.1. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In 2 unrelated, deceased probands of Indian descent with multiple mitochondrial dysfunctions syndrome-5 (MMDS5; 617613), Shukla et al. (2017) identified a homozygous missense mutation in the ISCA1 gene (E87K; 611006.0001). Molecular modeling predicted that the mutation would lead to destabilization of the protein. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Haplotype analysis suggested a founder effect. Functional studies of the variant and studies of patient cells were not performed. </p><p>In an Italian boy with MMDS5, Torraco et al. (2018) identified a homozygous missense mutation (V10G; 611006.0002) in the ISCA1 gene. The mutation was detected by next-generation sequencing of a mitochondrial-targeted gene panel and confirmed by Sanger sequencing. Both parents and an unaffected sib were heterozygous for the mutation. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Nilsson et al. (2009) found that targeted knockdown of Isca1 in zebrafish resulted in profound anemia. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
|
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</span>
|
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<strong>2 Selected Examples):</strong>
|
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0001 MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 5</strong>
|
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</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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ISCA1, GLU87LYS ({dbSNP SCV000328646})
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<br />
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SNP: rs776679653,
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gnomAD: rs776679653,
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ClinVar: RCV000497255, RCV000508655
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 unrelated probands of Indian descent with multiple mitochondrial dysfunctions syndrome-5 (MMDS5; 617613), Shukla et al. (2017) identified a homozygous c.259G-A transition (c.259G-A, NM_030940.3) in exon 4 of the ISCA1 gene, resulting in a glu87-to-lys (E87K) substitution at a conserved residue in the Fe-S biogenesis domain. Molecular modeling predicted that the mutation would lead to destabilization of the protein. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The mutation was not found in homozygous state in the 1000 Genomes Project or the Exome Variant Server databases or in an in-house exome database of 139 individuals from the same population; however, the variant was found at very low frequencies in heterozygous state in the ExAC and gnomAD databases. Both probands had a similarly affected sib, although biologic material was not available from the sibs. All of the children were deceased at the time of the report. Haplotype analysis suggested a founder effect. Functional studies of the variant and studies of patient cells were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 5</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ISCA1, VAL10GLY
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<br />
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SNP: rs1587823007,
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ClinVar: RCV000857321
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an Italian boy with multiple mitochondrial dysfunctions syndrome-5 (MMDS5; 617613), Torraco et al. (2018) identified a homozygous c.29T-G transversion (c.29T-G, NM_030940.3) in exon 1 of the ISCA1 gene, resulting in a val10-to-gly (V10G) substitution at a moderately conserved residue predicted to be located in the presequence part of the protein. The mutation was detected by next-generation sequencing of a mitochondrial-targeted gene panel and confirmed by Sanger sequencing. The parents were heterozygous for the mutation. An older sib died at 1 year of age with clinical features of MMDS5, but molecular testing was not performed. The mutation was not present in the dbSNP, ExAC, and EVS databases. Postmortem brain and muscle tissue from the patient had multiple defects of respiratory chain complex activities. Studies in patient fibroblasts showed reduction of ISCA1 protein content, reduction of the [4Fe-4S] cluster-containing proteins NDUFS1 (157655) and SDHB (185470), and reduction in ATP synthesis with succinate, malate, and pyruvate as substrates. Functional analysis of the ISCA1 protein containing the V10G mutation in HeLa cells showed decreased mitochondrial ISCA1 protein import, stability, and biologic function in the mitochondrial matrix. </p>
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<strong>REFERENCES</strong>
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Cozar-Castellano, I., del Valle Machargo, M., Trujillo, E., Arteaga, M. F., Gonzalez, T., Martin-Vasallo, P., Avila, J.
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<strong>hIscA: a protein implicated in the biogenesis of iron-sulfur clusters.</strong>
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[PubMed: 15262227]
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Nilsson, R., Schultz, I. J., Pierce, E. L., Soltis, K. A., Naranuntarat, A., Ward, D. M., Baughman, J. M., Paradkar, P. N., Kingsley, P. D., Culotta, V. C., Kaplan, J., Palis, J., Paw, B. H., Mootha, V. K.
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<strong>Discovery of genes essential for heme biosynthesis through large-scale gene expression analysis.</strong>
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Sheftel, A. D., Wilbrecht, C., Stehling, O., Niggemeyer, B., Elsasser, H.-P., Muhlenhoff, U., Lill, R.
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<strong>The human mitochondrial ISCA1, ISCA2, and IBA57 proteins are required for [4Fe-4S] protein maturation.</strong>
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Molec. Biol. Cell 23: 1157-1166, 2012.
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[PubMed: 22323289]
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[Full Text: https://doi.org/10.1091/mbc.E11-09-0772]
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Shukla, A., Hebbar, M., Srivastava, A., Kadavigere, R., Upadhyai, P., Kanthi, A., Brandau, O., Bielas, S., Girisha, K. M.
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<strong>Homozygous p.(Glu8Lys) variant in ISCA1 is associated with a multiple mitochondrial dysfunctions syndrome.</strong>
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J. Hum. Genet. 62: 723-727, 2017.
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[PubMed: 28356563]
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[Full Text: https://doi.org/10.1038/jhg.2017.35]
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Song, D., Tu, Z., Lee, F. S.
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<strong>Human ISCA1 interacts with IOP1/NARFL and functions in both cytosolic and mitochondrial iron-sulfur protein biogenesis.</strong>
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J. Biol. Chem. 284: 35297-35307, 2009.
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[PubMed: 19864422]
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[Full Text: https://doi.org/10.1074/jbc.M109.040014]
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Torraco, A., Stehling, O., Stumpfig, C., Rosser, R., De Rasmo, D., Fiermonte, G., Verrigni, D., Rizza, T., Vozza, A., Di Nottia, M., Diodato, D., Martinelli, D., Piemonte, F., Dionisi-Vici, C., Bertini, E., Lill, R., Carrozzo, R.
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<strong>ISCA1 mutation in a patient with infantile-onset leukodystrophy causes defects in mitochondrial [4Fe-4S] proteins.</strong>
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Hum. Molec. Genet. 27: 2739-2754, 2018.
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[PubMed: 29767723]
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[Full Text: https://doi.org/10.1093/hmg/ddy183]
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Hilary J. Vernon - updated : 07/08/2020<br>Cassandra L. Kniffin - updated : 08/09/2017<br>Paul J. Converse - updated : 8/20/2013<br>Paul J. Converse - updated : 7/18/2013
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