2973 lines
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Entry
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- *600783 - HISTIDYL-tRNA SYNTHETASE 2; HARS2
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- OMIM
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<p>
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<span class="h4">*600783</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/600783">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<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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</ul>
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<div id="mimFloatingLinksMenu">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000112855;t=ENST00000230771" 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=23438" 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=600783" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000112855;t=ENST00000230771" 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_001278731,NM_001278732,NM_001363535,NM_001363536,NM_012208" 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_012208" 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=600783" 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=02871&isoform_id=02871_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/HARS2" 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/899106,899109,1351156,14043376,15029520,15929049,119582423,119582424,189066563,194373407,194373607,194384846,194389672,523567531,523567533,1391723582,1391723599" 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/P49590" 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=23438" 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=ENSG00000112855;t=ENST00000230771" 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=HARS2" 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=HARS2" 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+23438" 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/HARS2" 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:23438" 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/23438" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr5&hgg_gene=ENST00000230771.9&hgg_start=140691455&hgg_end=140699305&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://search.clinicalgenome.org/kb/genes/HGNC:4817" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/hars2" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=600783[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=600783[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/ENSG00000112855" 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=HARS2" 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=HARS2" 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=HARS2" 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=HARS2&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/PA29192" 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:4817" 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/FBgn0027087.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1918041" 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/HARS2#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:1918041" 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/23438/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=23438" 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=WBGene00002001;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-040912-152" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:23438" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=HARS2&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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600783
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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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HISTIDYL-tRNA SYNTHETASE 2; HARS2
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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>
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<span class="mim-font">
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HISTIDYL-tRNA SYNTHETASE, MITOCHONDRIAL<br />
|
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MITOCHONDRIAL HISRS<br />
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HISTIDYL-tRNA SYNTHETASE-LIKE; HARSL<br />
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HARS-RELATED GENE; HARSR<br />
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HO3
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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=HARS2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">HARS2</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/5/545?start=-3&limit=10&highlight=545">5q31.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr5:140691455-140699305&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">5:140,691,455-140,699,305</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/5/545?start=-3&limit=10&highlight=545">
|
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5q31.3
|
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</a>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
Perrault syndrome 2
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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|
|
<a href="/entry/614926"> 614926 </a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/600783" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/600783" 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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<p />
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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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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<p>The HARS2 gene encodes a histidyl tRNA synthetase, a highly conserved protein that functions in mitochondria (summary by <a href="#5" class="mim-tip-reference" title="Pierce, S. B., Chisholm, K. M., Lynch, E. D., Lee, M. K., Walsh, T., Opitz, J. M., Li, W., Klevit, R. E., King, M.-C. <strong>Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome.</strong> Proc. Nat. Acad. Sci. 108: 6543-6548, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21464306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21464306</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21464306[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/10.1073/pnas.1103471108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21464306">Pierce et al., 2011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21464306" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#3" class="mim-tip-reference" title="O'Hanlon, T. P., Raben, N., Miller, F. W. <strong>A novel gene oriented in a head-to-head configuration with the human histidyl-tRNA synthetase (HRS) gene encodes an mRNA that predicts a polypeptide homologous to HRS.</strong> Biochem. Biophys. Res. Commun. 210: 556-566, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7755634/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7755634</a>] [<a href="https://doi.org/10.1006/bbrc.1995.1696" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7755634">O'Hanlon et al. (1995)</a> identified the HARS2 gene, which they called HO3, oriented head-to-head with the HARS gene (<a href="/entry/142810">142810</a>). The deduced 506-amino acid HO3 protein has a calculated molecular mass of 56.9 kD. HO3 shares 72% amino acid identity with HARS. Both proteins contain 3 motifs conserved among class II aminoacyl-tRNA synthetases and 2 signature regions of histidyl-tRNA synthetases. However, HARS and HARS2 have divergent N-terminal domains that are encoded by the first 2 exons of each gene. Northern blot analysis detected a 2.5-kb HO3 transcript that was highly expressed in heart, skeletal muscle, and kidney, with lower expression in brain and liver. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7755634" 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 5-prime RACE with a human kidney cDNA library, <a href="#2" class="mim-tip-reference" title="O'Hanlon, T. P., Miller, F. W. <strong>Genomic organization, transcriptional mapping, and evolutionary implications of the human bi-directional histidyl-tRNA synthetase locus (HARS/HARSL).</strong> Biochem. Biophys. Res. Commun. 294: 609-614, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12056811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12056811</a>] [<a href="https://doi.org/10.1016/S0006-291X(02)00525-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12056811">O'Hanlon and Miller (2002)</a> identified several HARSL transcripts that differed only in the lengths of their 5-prime UTRs. They also identified HARSL transcripts containing an alternatively spliced 91-bp exon within their 5-prime UTRs. <a href="#2" class="mim-tip-reference" title="O'Hanlon, T. P., Miller, F. W. <strong>Genomic organization, transcriptional mapping, and evolutionary implications of the human bi-directional histidyl-tRNA synthetase locus (HARS/HARSL).</strong> Biochem. Biophys. Res. Commun. 294: 609-614, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12056811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12056811</a>] [<a href="https://doi.org/10.1016/S0006-291X(02)00525-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12056811">O'Hanlon and Miller (2002)</a> reported that the mouse and human HARSL proteins share 83.9% amino acid identity. They noted that the HARSL protein lacks 60 N-terminal amino acids found in HARS that are necessary for enzymatic activity, suggesting that HARSL may not function as a tRNA synthetase. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12056811" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By searching databases for aminoacyl-tRNA synthetases containing a mitochondrial targeting sequence, <a href="#1" class="mim-tip-reference" title="Bonnefond, L., Fender, A., Rudinger-Thirion, J., Giege, R., Florentz, C., Sissler, M. <strong>Toward the full set of human mitochondrial aminoacyl-tRNA synthetases: characterization of AspRS and TyrRS.</strong> Biochemistry 44: 4805-4816, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15779907/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15779907</a>] [<a href="https://doi.org/10.1021/bi047527z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15779907">Bonnefond et al. (2005)</a> identified HARS2, which they called mitochondrial HISRS. The deduced 506-amino acid protein has an N-terminal mitochondrial targeting signal with a predicted cleavage site after residue 34. HARS2 has characteristics of a class II mitochondrial aminoacyl-tRNA synthetase and is expected to function as a dimer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15779907" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Pierce, S. B., Chisholm, K. M., Lynch, E. D., Lee, M. K., Walsh, T., Opitz, J. M., Li, W., Klevit, R. E., King, M.-C. <strong>Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome.</strong> Proc. Nat. Acad. Sci. 108: 6543-6548, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21464306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21464306</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21464306[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/10.1073/pnas.1103471108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21464306">Pierce et al. (2011)</a> found high expression of the HARS2 gene in the mitochondria of mammalian cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21464306" 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="O'Hanlon, T. P., Miller, F. W. <strong>Genomic organization, transcriptional mapping, and evolutionary implications of the human bi-directional histidyl-tRNA synthetase locus (HARS/HARSL).</strong> Biochem. Biophys. Res. Commun. 294: 609-614, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12056811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12056811</a>] [<a href="https://doi.org/10.1016/S0006-291X(02)00525-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12056811">O'Hanlon and Miller (2002)</a> determined that the HARS2 gene contains 13 exons and spans about 7.9 kb. The HARS and HARS2 genes share a bidirectional promoter that lacks TATA and CAAT boxes. Both genes use multiple transcriptional start sites. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12056811" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Bonnefond, L., Fender, A., Rudinger-Thirion, J., Giege, R., Florentz, C., Sissler, M. <strong>Toward the full set of human mitochondrial aminoacyl-tRNA synthetases: characterization of AspRS and TyrRS.</strong> Biochemistry 44: 4805-4816, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15779907/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15779907</a>] [<a href="https://doi.org/10.1021/bi047527z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15779907">Bonnefond et al. (2005)</a> reported that the HARS2 gene contains 13 exons and spans 6.9 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15779907" 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="#3" class="mim-tip-reference" title="O'Hanlon, T. P., Raben, N., Miller, F. W. <strong>A novel gene oriented in a head-to-head configuration with the human histidyl-tRNA synthetase (HRS) gene encodes an mRNA that predicts a polypeptide homologous to HRS.</strong> Biochem. Biophys. Res. Commun. 210: 556-566, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7755634/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7755634</a>] [<a href="https://doi.org/10.1006/bbrc.1995.1696" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7755634">O'Hanlon et al. (1995)</a> mapped the HARS2 gene to chromosome 5, where it is oriented head-to-head with the HARS gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7755634" 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="#2" class="mim-tip-reference" title="O'Hanlon, T. P., Miller, F. W. <strong>Genomic organization, transcriptional mapping, and evolutionary implications of the human bi-directional histidyl-tRNA synthetase locus (HARS/HARSL).</strong> Biochem. Biophys. Res. Commun. 294: 609-614, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12056811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12056811</a>] [<a href="https://doi.org/10.1016/S0006-291X(02)00525-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12056811">O'Hanlon and Miller (2002)</a> mapped the HARS and HARS2 genes to chromosome 5q31.3 by genomic sequence analysis. The ORFs of HARS and HARS2 are separated by 344 bp. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12056811" 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 affected members of a family of European descent with Perrault syndrome-2 (PRLTS2; <a href="/entry/614926">614926</a>), originally reported by <a href="#4" class="mim-tip-reference" title="Pallister, P. D., Opitz, J. M. <strong>The Perrault syndrome: autosomal recessive ovarian dysgenesis with facultative, non-sex-limited sensorineural deafness.</strong> Am. J. Med. Genet. 4: 239-246, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/517579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">517579</a>] [<a href="https://doi.org/10.1002/ajmg.1320040306" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="517579">Pallister and Opitz (1979)</a>, <a href="#5" class="mim-tip-reference" title="Pierce, S. B., Chisholm, K. M., Lynch, E. D., Lee, M. K., Walsh, T., Opitz, J. M., Li, W., Klevit, R. E., King, M.-C. <strong>Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome.</strong> Proc. Nat. Acad. Sci. 108: 6543-6548, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21464306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21464306</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21464306[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/10.1073/pnas.1103471108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21464306">Pierce et al. (2011)</a> identified compound heterozygosity for 2 mutations in the HARS2 gene (<a href="#0001">600783.0001</a> and <a href="#0002">600783.0002</a>). The mutations, which were found by linkage analysis followed by candidate gene sequencing, were shown to cause decreased enzyme activity. Affected females had sensorineural deafness, primary amenorrhea, streak gonads, and infertility, whereas affected males had deafness, normal pubertal development, and were fertile. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=517579+21464306" 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="#6" class="mim-tip-reference" title="Zou, S., Mei, X., Yang, W., Zhu, R., Yang, T., Hu, H. <strong>Whole-exome sequencing identifies rare pathogenic and candidate variants in sporadic Chinese Han deaf patients.</strong> Clin. Genet. 97: 352-356, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31486067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31486067</a>] [<a href="https://doi.org/10.1111/cge.13638" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31486067">Zou et al. (2020)</a> identified compound heterozygous mutations in the HARS gene (R191Q, <a href="#0003">600783.0003</a> and R208C, <a href="#0004">600783.0004</a>) in a Han Chinese patient (D2092) with isolated severe to profound sensorineural hearing loss. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31486067" 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="#5" class="mim-tip-reference" title="Pierce, S. B., Chisholm, K. M., Lynch, E. D., Lee, M. K., Walsh, T., Opitz, J. M., Li, W., Klevit, R. E., King, M.-C. <strong>Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome.</strong> Proc. Nat. Acad. Sci. 108: 6543-6548, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21464306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21464306</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21464306[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/10.1073/pnas.1103471108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21464306">Pierce et al. (2011)</a> demonstrated that 50% knockdown of the Hars1 gene in C. elegans resulted in severe gonadal defects, including smaller, narrower gonads and absence of oocytes or fertilized eggs in the majority of animals. The animals were almost completely sterile. The loss of fertility apparently resulted from increased apoptosis of germ cells. Complete knockdown of the Hars1 gene resulted in arrested development at the L2 larvae stage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21464306" 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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<span id="mimAllelicVariantsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>4 Selected Examples</a>):</strong>
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<a href="/allelicVariants/600783" class="btn btn-default" role="button"> Table View </a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=600783[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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<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> rs397515410 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515410;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/rs397515410?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=rs397515410" 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=rs397515410" 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=RCV000032820 OR RCV002468984 OR RCV002513308" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032820, RCV002468984, RCV002513308" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032820...</a>
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<p>In affected members of a family of European descent with Perrault syndrome-2 (PRLTS2; <a href="/entry/614926">614926</a>), originally reported by <a href="#4" class="mim-tip-reference" title="Pallister, P. D., Opitz, J. M. <strong>The Perrault syndrome: autosomal recessive ovarian dysgenesis with facultative, non-sex-limited sensorineural deafness.</strong> Am. J. Med. Genet. 4: 239-246, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/517579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">517579</a>] [<a href="https://doi.org/10.1002/ajmg.1320040306" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="517579">Pallister and Opitz (1979)</a>, <a href="#5" class="mim-tip-reference" title="Pierce, S. B., Chisholm, K. M., Lynch, E. D., Lee, M. K., Walsh, T., Opitz, J. M., Li, W., Klevit, R. E., King, M.-C. <strong>Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome.</strong> Proc. Nat. Acad. Sci. 108: 6543-6548, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21464306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21464306</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21464306[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/10.1073/pnas.1103471108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21464306">Pierce et al. (2011)</a> identified compound heterozygosity for 2 mutations in the HARS2 gene: a paternally inherited 598C-G transversion in exon 6 resulting in a leu200-to-val (L200V) substitution at a highly conserved residue, and a maternally inherited 1102G-T transversion in exon 10 resulting in a val368-to-leu (V368L; <a href="#0002">600783.0002</a>) substitution at a highly conserved residue. The mutations were found by linkage analysis followed by candidate gene sequencing. Neither mutation was found in 1,942 control individuals. Study of patient lymphoblasts showed that the 598C-G mutation also created an alternative splice site, resulting in an in-frame deletion of 12 codons in exon 6 (delta200-211). The deletion transcript was present at much lower levels in the unaffected father compared to the affected children. Both mutant missense proteins were expressed, could dimerize, and localized to the mitochondria in mammalian cells, but the deletion transcript was poorly expressed, suggesting that it is unstable. Both missense mutations had significantly decreased enzymatic activity compared to wildtype, with the V368L mutation showing a more severe effect. Modeling of the homologous mutations in yeast also indicated that the V368L mutant had a more severe effect on enzyme activity. Based on the functions of mitochondrial tRNA synthetases and cellular defects resulting from their mutation, <a href="#5" class="mim-tip-reference" title="Pierce, S. B., Chisholm, K. M., Lynch, E. D., Lee, M. K., Walsh, T., Opitz, J. M., Li, W., Klevit, R. E., King, M.-C. <strong>Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome.</strong> Proc. Nat. Acad. Sci. 108: 6543-6548, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21464306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21464306</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21464306[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/10.1073/pnas.1103471108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21464306">Pierce et al. (2011)</a> speculated that mutations in HARS2 result in decreased mitochondrial translation and respiratory chain defects in affected tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=517579+21464306" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs376177973 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs376177973;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/rs376177973?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=rs376177973" 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=rs376177973" 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=RCV000206915 OR RCV002517027" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000206915, RCV002517027" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000206915...</a>
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<p>For discussion of the val368-to-leu (V368L) mutation in the HARS2 gene that was found in compound heterozygous state in affected members of a family with Perrault syndrome-2 (PRLTS2; <a href="/entry/614926">614926</a>) by <a href="#5" class="mim-tip-reference" title="Pierce, S. B., Chisholm, K. M., Lynch, E. D., Lee, M. K., Walsh, T., Opitz, J. M., Li, W., Klevit, R. E., King, M.-C. <strong>Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome.</strong> Proc. Nat. Acad. Sci. 108: 6543-6548, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21464306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21464306</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21464306[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/10.1073/pnas.1103471108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21464306">Pierce et al. (2011)</a>, see <a href="#0001">600783.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21464306" 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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HARS2, ARG191GLN
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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> rs1229581230 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1229581230;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/rs1229581230?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=rs1229581230" 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=rs1229581230" 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=RCV001261943" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001261943" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001261943</a>
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<p>In a Han Chinese patient (D2092) with Perrault syndrome-2 (PRLTS2; <a href="/entry/614926">614926</a>) with isolated severe to profound sensorineural hearing loss, <a href="#6" class="mim-tip-reference" title="Zou, S., Mei, X., Yang, W., Zhu, R., Yang, T., Hu, H. <strong>Whole-exome sequencing identifies rare pathogenic and candidate variants in sporadic Chinese Han deaf patients.</strong> Clin. Genet. 97: 352-356, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31486067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31486067</a>] [<a href="https://doi.org/10.1111/cge.13638" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31486067">Zou et al. (2020)</a> identified compound heterozygous mutations in the HARS gene: a c.572G-A transition (c.572G-A, NM_001278731), resulting in an arg191-to-gln (R191Q) substitution, and a c.622C-T transition, resulting in an arg208-to-cys (R208C; 600783.0004) substitution. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. The mutations were shown to be in trans, with each parent confirmed to carry one mutation. The R191Q variant was not reported in the 1000 Genomes Project database; it was reported in the gnomAD database at a frequency of 0.00000797 and was identified in an internal database of 414 Han Chinese control subjects at a frequency of 0.00023652. The R208C variant was not reported in the 1000 Genomes Project database or in an internal database of 2,114 Han Chinese control subjects, but was reported in the gnomAD database at a frequency of 0.00001593. Functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31486067" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs749799529 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs749799529;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/rs749799529?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=rs749799529" 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=rs749799529" 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=RCV000199488 OR RCV000767024 OR RCV001261944" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000199488, RCV000767024, RCV001261944" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000199488...</a>
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<p>For discussion of the c.622C-T transition (c.622C-T, NM_001278731) in the HARS2 gene, resulting in an arg208-to-cys (R208C) substitution, that was found in compound heterozygous state in a Han Chinese patient with Perrault syndrome-2 (PRLTS2; <a href="/entry/614926">614926</a>) by <a href="#6" class="mim-tip-reference" title="Zou, S., Mei, X., Yang, W., Zhu, R., Yang, T., Hu, H. <strong>Whole-exome sequencing identifies rare pathogenic and candidate variants in sporadic Chinese Han deaf patients.</strong> Clin. Genet. 97: 352-356, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31486067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31486067</a>] [<a href="https://doi.org/10.1111/cge.13638" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31486067">Zou et al. (2020)</a>, see <a href="#0003">600783.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31486067" 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="Bonnefond2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Bonnefond, L., Fender, A., Rudinger-Thirion, J., Giege, R., Florentz, C., Sissler, M.
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<strong>Toward the full set of human mitochondrial aminoacyl-tRNA synthetases: characterization of AspRS and TyrRS.</strong>
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Biochemistry 44: 4805-4816, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15779907/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15779907</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15779907" 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/10.1021/bi047527z" target="_blank">Full Text</a>]
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<a id="O'Hanlon2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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O'Hanlon, T. P., Miller, F. W.
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<strong>Genomic organization, transcriptional mapping, and evolutionary implications of the human bi-directional histidyl-tRNA synthetase locus (HARS/HARSL).</strong>
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Biochem. Biophys. Res. Commun. 294: 609-614, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12056811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12056811</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12056811" 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/S0006-291X(02)00525-9" target="_blank">Full Text</a>]
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<a id="3" class="mim-anchor"></a>
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<a id="O'Hanlon1995" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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O'Hanlon, T. P., Raben, N., Miller, F. W.
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<strong>A novel gene oriented in a head-to-head configuration with the human histidyl-tRNA synthetase (HRS) gene encodes an mRNA that predicts a polypeptide homologous to HRS.</strong>
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Biochem. Biophys. Res. Commun. 210: 556-566, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7755634/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7755634</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7755634" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/bbrc.1995.1696" target="_blank">Full Text</a>]
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<a id="4" class="mim-anchor"></a>
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<a id="Pallister1979" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Pallister, P. D., Opitz, J. M.
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<strong>The Perrault syndrome: autosomal recessive ovarian dysgenesis with facultative, non-sex-limited sensorineural deafness.</strong>
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Am. J. Med. Genet. 4: 239-246, 1979.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/517579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">517579</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=517579" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320040306" target="_blank">Full Text</a>]
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<a id="Pierce2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Pierce, S. B., Chisholm, K. M., Lynch, E. D., Lee, M. K., Walsh, T., Opitz, J. M., Li, W., Klevit, R. E., King, M.-C.
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<strong>Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome.</strong>
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Proc. Nat. Acad. Sci. 108: 6543-6548, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21464306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21464306</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21464306[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=21464306" 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/10.1073/pnas.1103471108" target="_blank">Full Text</a>]
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<a id="Zou2020" class="mim-anchor"></a>
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<p class="mim-text-font">
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Zou, S., Mei, X., Yang, W., Zhu, R., Yang, T., Hu, H.
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<strong>Whole-exome sequencing identifies rare pathogenic and candidate variants in sporadic Chinese Han deaf patients.</strong>
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Clin. Genet. 97: 352-356, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31486067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31486067</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31486067" 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/10.1111/cge.13638" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 10/26/2020
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 11/14/2012<br>Patricia A. Hartz - updated : 9/11/2009<br>Patricia A. Hartz - updated : 5/21/2009
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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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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Alan F. Scott : 9/19/1995
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<span class="mim-text-font">
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carol : 10/26/2020
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<div class="row collapse" id="mimCollapseEditHistory">
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<span class="mim-text-font">
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carol : 07/20/2016<br>carol : 09/24/2015<br>carol : 9/16/2015<br>mcolton : 8/18/2015<br>alopez : 1/24/2013<br>alopez : 11/15/2012<br>ckniffin : 11/14/2012<br>mgross : 9/15/2009<br>terry : 9/11/2009<br>mgross : 5/26/2009<br>terry : 5/21/2009<br>carol : 3/30/2000<br>mark : 4/7/1996<br>mark : 9/19/1995
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<strong>*</strong> 600783
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<h3>
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<span class="mim-font">
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HISTIDYL-tRNA SYNTHETASE 2; HARS2
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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HISTIDYL-tRNA SYNTHETASE, MITOCHONDRIAL<br />
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MITOCHONDRIAL HISRS<br />
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HISTIDYL-tRNA SYNTHETASE-LIKE; HARSL<br />
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HARS-RELATED GENE; HARSR<br />
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HO3
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: HARS2</em></strong>
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<strong>
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<em>
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Cytogenetic location: 5q31.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 5:140,691,455-140,699,305 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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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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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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<td rowspan="1">
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<span class="mim-font">
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5q31.3
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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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Perrault syndrome 2
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</span>
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</td>
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<td>
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<span class="mim-font">
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614926
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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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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The HARS2 gene encodes a histidyl tRNA synthetase, a highly conserved protein that functions in mitochondria (summary by Pierce et al., 2011). </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>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>O'Hanlon et al. (1995) identified the HARS2 gene, which they called HO3, oriented head-to-head with the HARS gene (142810). The deduced 506-amino acid HO3 protein has a calculated molecular mass of 56.9 kD. HO3 shares 72% amino acid identity with HARS. Both proteins contain 3 motifs conserved among class II aminoacyl-tRNA synthetases and 2 signature regions of histidyl-tRNA synthetases. However, HARS and HARS2 have divergent N-terminal domains that are encoded by the first 2 exons of each gene. Northern blot analysis detected a 2.5-kb HO3 transcript that was highly expressed in heart, skeletal muscle, and kidney, with lower expression in brain and liver. </p><p>Using 5-prime RACE with a human kidney cDNA library, O'Hanlon and Miller (2002) identified several HARSL transcripts that differed only in the lengths of their 5-prime UTRs. They also identified HARSL transcripts containing an alternatively spliced 91-bp exon within their 5-prime UTRs. O'Hanlon and Miller (2002) reported that the mouse and human HARSL proteins share 83.9% amino acid identity. They noted that the HARSL protein lacks 60 N-terminal amino acids found in HARS that are necessary for enzymatic activity, suggesting that HARSL may not function as a tRNA synthetase. </p><p>By searching databases for aminoacyl-tRNA synthetases containing a mitochondrial targeting sequence, Bonnefond et al. (2005) identified HARS2, which they called mitochondrial HISRS. The deduced 506-amino acid protein has an N-terminal mitochondrial targeting signal with a predicted cleavage site after residue 34. HARS2 has characteristics of a class II mitochondrial aminoacyl-tRNA synthetase and is expected to function as a dimer. </p><p>Pierce et al. (2011) found high expression of the HARS2 gene in the mitochondria of mammalian cells. </p>
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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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</h4>
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<span class="mim-text-font">
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<p>O'Hanlon and Miller (2002) determined that the HARS2 gene contains 13 exons and spans about 7.9 kb. The HARS and HARS2 genes share a bidirectional promoter that lacks TATA and CAAT boxes. Both genes use multiple transcriptional start sites. </p><p>Bonnefond et al. (2005) reported that the HARS2 gene contains 13 exons and spans 6.9 kb. </p>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By genomic sequence analysis, O'Hanlon et al. (1995) mapped the HARS2 gene to chromosome 5, where it is oriented head-to-head with the HARS gene. </p><p>O'Hanlon and Miller (2002) mapped the HARS and HARS2 genes to chromosome 5q31.3 by genomic sequence analysis. The ORFs of HARS and HARS2 are separated by 344 bp. </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</h4>
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<span class="mim-text-font">
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<p>In affected members of a family of European descent with Perrault syndrome-2 (PRLTS2; 614926), originally reported by Pallister and Opitz (1979), Pierce et al. (2011) identified compound heterozygosity for 2 mutations in the HARS2 gene (600783.0001 and 600783.0002). The mutations, which were found by linkage analysis followed by candidate gene sequencing, were shown to cause decreased enzyme activity. Affected females had sensorineural deafness, primary amenorrhea, streak gonads, and infertility, whereas affected males had deafness, normal pubertal development, and were fertile. </p><p>Zou et al. (2020) identified compound heterozygous mutations in the HARS gene (R191Q, 600783.0003 and R208C, 600783.0004) in a Han Chinese patient (D2092) with isolated severe to profound sensorineural hearing loss. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. </p>
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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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<span class="mim-text-font">
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<p>Pierce et al. (2011) demonstrated that 50% knockdown of the Hars1 gene in C. elegans resulted in severe gonadal defects, including smaller, narrower gonads and absence of oocytes or fertilized eggs in the majority of animals. The animals were almost completely sterile. The loss of fertility apparently resulted from increased apoptosis of germ cells. Complete knockdown of the Hars1 gene resulted in arrested development at the L2 larvae stage. </p>
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<br />
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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>4 Selected Examples):</strong>
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</span>
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</h4>
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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 PERRAULT SYNDROME 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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HARS2, LEU200VAL
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<br />
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SNP: rs397515410,
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gnomAD: rs397515410,
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ClinVar: RCV000032820, RCV002468984, RCV002513308
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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 affected members of a family of European descent with Perrault syndrome-2 (PRLTS2; 614926), originally reported by Pallister and Opitz (1979), Pierce et al. (2011) identified compound heterozygosity for 2 mutations in the HARS2 gene: a paternally inherited 598C-G transversion in exon 6 resulting in a leu200-to-val (L200V) substitution at a highly conserved residue, and a maternally inherited 1102G-T transversion in exon 10 resulting in a val368-to-leu (V368L; 600783.0002) substitution at a highly conserved residue. The mutations were found by linkage analysis followed by candidate gene sequencing. Neither mutation was found in 1,942 control individuals. Study of patient lymphoblasts showed that the 598C-G mutation also created an alternative splice site, resulting in an in-frame deletion of 12 codons in exon 6 (delta200-211). The deletion transcript was present at much lower levels in the unaffected father compared to the affected children. Both mutant missense proteins were expressed, could dimerize, and localized to the mitochondria in mammalian cells, but the deletion transcript was poorly expressed, suggesting that it is unstable. Both missense mutations had significantly decreased enzymatic activity compared to wildtype, with the V368L mutation showing a more severe effect. Modeling of the homologous mutations in yeast also indicated that the V368L mutant had a more severe effect on enzyme activity. Based on the functions of mitochondrial tRNA synthetases and cellular defects resulting from their mutation, Pierce et al. (2011) speculated that mutations in HARS2 result in decreased mitochondrial translation and respiratory chain defects in affected tissues. </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 PERRAULT SYNDROME 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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HARS2, VAL368LEU
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<br />
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SNP: rs376177973,
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gnomAD: rs376177973,
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ClinVar: RCV000206915, RCV002517027
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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>For discussion of the val368-to-leu (V368L) mutation in the HARS2 gene that was found in compound heterozygous state in affected members of a family with Perrault syndrome-2 (PRLTS2; 614926) by Pierce et al. (2011), see 600783.0001. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 PERRAULT SYNDROME 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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HARS2, ARG191GLN
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<br />
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SNP: rs1229581230,
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gnomAD: rs1229581230,
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ClinVar: RCV001261943
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In a Han Chinese patient (D2092) with Perrault syndrome-2 (PRLTS2; 614926) with isolated severe to profound sensorineural hearing loss, Zou et al. (2020) identified compound heterozygous mutations in the HARS gene: a c.572G-A transition (c.572G-A, NM_001278731), resulting in an arg191-to-gln (R191Q) substitution, and a c.622C-T transition, resulting in an arg208-to-cys (R208C; 600783.0004) substitution. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. The mutations were shown to be in trans, with each parent confirmed to carry one mutation. The R191Q variant was not reported in the 1000 Genomes Project database; it was reported in the gnomAD database at a frequency of 0.00000797 and was identified in an internal database of 414 Han Chinese control subjects at a frequency of 0.00023652. The R208C variant was not reported in the 1000 Genomes Project database or in an internal database of 2,114 Han Chinese control subjects, but was reported in the gnomAD database at a frequency of 0.00001593. Functional studies 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">
|
|
<strong>.0004 PERRAULT SYNDROME 2</strong>
|
|
</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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HARS2, ARG208CYS
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<br />
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|
SNP: rs749799529,
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|
|
gnomAD: rs749799529,
|
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|
|
ClinVar: RCV000199488, RCV000767024, RCV001261944
|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>For discussion of the c.622C-T transition (c.622C-T, NM_001278731) in the HARS2 gene, resulting in an arg208-to-cys (R208C) substitution, that was found in compound heterozygous state in a Han Chinese patient with Perrault syndrome-2 (PRLTS2; 614926) by Zou et al. (2020), see 600783.0003. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Bonnefond, L., Fender, A., Rudinger-Thirion, J., Giege, R., Florentz, C., Sissler, M.
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<strong>Toward the full set of human mitochondrial aminoacyl-tRNA synthetases: characterization of AspRS and TyrRS.</strong>
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Biochemistry 44: 4805-4816, 2005.
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[PubMed: 15779907]
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[Full Text: https://doi.org/10.1021/bi047527z]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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O'Hanlon, T. P., Miller, F. W.
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<strong>Genomic organization, transcriptional mapping, and evolutionary implications of the human bi-directional histidyl-tRNA synthetase locus (HARS/HARSL).</strong>
|
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Biochem. Biophys. Res. Commun. 294: 609-614, 2002.
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[PubMed: 12056811]
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[Full Text: https://doi.org/10.1016/S0006-291X(02)00525-9]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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O'Hanlon, T. P., Raben, N., Miller, F. W.
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<strong>A novel gene oriented in a head-to-head configuration with the human histidyl-tRNA synthetase (HRS) gene encodes an mRNA that predicts a polypeptide homologous to HRS.</strong>
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Biochem. Biophys. Res. Commun. 210: 556-566, 1995.
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[PubMed: 7755634]
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[Full Text: https://doi.org/10.1006/bbrc.1995.1696]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Pallister, P. D., Opitz, J. M.
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<strong>The Perrault syndrome: autosomal recessive ovarian dysgenesis with facultative, non-sex-limited sensorineural deafness.</strong>
|
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Am. J. Med. Genet. 4: 239-246, 1979.
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[PubMed: 517579]
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[Full Text: https://doi.org/10.1002/ajmg.1320040306]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Pierce, S. B., Chisholm, K. M., Lynch, E. D., Lee, M. K., Walsh, T., Opitz, J. M., Li, W., Klevit, R. E., King, M.-C.
|
|
<strong>Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome.</strong>
|
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Proc. Nat. Acad. Sci. 108: 6543-6548, 2011.
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[PubMed: 21464306]
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[Full Text: https://doi.org/10.1073/pnas.1103471108]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Zou, S., Mei, X., Yang, W., Zhu, R., Yang, T., Hu, H.
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<strong>Whole-exome sequencing identifies rare pathogenic and candidate variants in sporadic Chinese Han deaf patients.</strong>
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Clin. Genet. 97: 352-356, 2020.
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[PubMed: 31486067]
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[Full Text: https://doi.org/10.1111/cge.13638]
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</li>
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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 10/26/2020<br>Cassandra L. Kniffin - updated : 11/14/2012<br>Patricia A. Hartz - updated : 9/11/2009<br>Patricia A. Hartz - updated : 5/21/2009
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</span>
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</div>
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Alan F. Scott : 9/19/1995
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Edit History:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 10/26/2020<br>carol : 07/20/2016<br>carol : 09/24/2015<br>carol : 9/16/2015<br>mcolton : 8/18/2015<br>alopez : 1/24/2013<br>alopez : 11/15/2012<br>ckniffin : 11/14/2012<br>mgross : 9/15/2009<br>terry : 9/11/2009<br>mgross : 5/26/2009<br>terry : 5/21/2009<br>carol : 3/30/2000<br>mark : 4/7/1996<br>mark : 9/19/1995
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