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<title>
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Entry
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- *142810 - HISTIDYL-tRNA SYNTHETASE 1; HARS1
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- OMIM
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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Advanced Search
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<a href="/search/advanced/entry"> OMIM </a>
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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<a href="/search/advanced/geneMap"> Gene Map </a>
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<div class="row">
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<p />
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<p>
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<span class="h4">*142810</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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</li>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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<li role="presentation">
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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>
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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>
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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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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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</li>
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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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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/142810">Table View</a>
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</li>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
|
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000170445;t=ENST00000504156" 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=3035" 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=142810" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000170445;t=ENST00000504156" 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_001258040,NM_001258041,NM_001258042,NM_001289092,NM_001289093,NM_001289094,NM_002109" 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_002109" 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=142810" 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=00827&isoform_id=00827_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/HARS1" 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/32458,32460,135123,431312,899107,6996014,15080052,51873908,62766469,119582425,119582426,119582427,193784950,194374235,194375508,194379338,194379722,194383532,384475552,384475554,384475556,574278766,574278942,574279253" 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/P12081" 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=3035" 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=ENSG00000170445;t=ENST00000504156" 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=HARS1" 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=HARS1" 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+3035" 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/HARS1" 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:3035" 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/3035" 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=ENST00000504156.7&hgg_start=140673905&hgg_end=140691370&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
|
|
<span class="panel-title">
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<span class="small">
|
|
<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:4816" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=142810[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=142810[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/ENSG00000170445" 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=HARS1" 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=HARS1" 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=HARS1" 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=HARS1&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/PA29191" 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:4816" 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:108087" 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/HARS1#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:108087" 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/3035/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=3035" 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">
|
|
<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:3035" 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=HARS1&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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|
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<a id="title" class="mim-anchor"></a>
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<div>
|
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 1172634009<br />
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">ICD+</a>
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
|
142810
|
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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 1; HARS1
|
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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">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
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</p>
|
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</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
HARS<br />
|
|
HRS<br />
|
|
HISRS
|
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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>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=HARS1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">HARS1</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>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/5/544?start=-3&limit=10&highlight=544">5q31.3</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr5:140673905-140691370&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'})">5:140,673,905-140,691,370</a> </span>
|
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</em>
|
|
</strong>
|
|
<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 />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
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|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=616625,614504" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
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Phenotype <br /> mapping key
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PheneGene Graphics <span class="caret"></span>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>HARS catalyzes the covalent ligation of histidine to its cognate tRNA as an early step in protein biosynthesis (<a href="#3" 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>). <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><a href="#4" 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> noted that HARS and HARS2 (<a href="/entry/600783">600783</a>), which they called HO3, are oriented in a head-to-head configuration and share a bidirectional promoter. They reported that the deduced 509-amino acid HARS protein shares 72% amino acid identity with HARS2. 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. HARS has a calculated molecular mass of 57.4 kD. Northern blot analysis detected a 2.0-kb HARS transcript that was highly expressed in heart, brain, liver, and kidney. <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="#3" 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 HARS transcripts that differed only in the lengths of their 5-prime UTRs. <a href="#3" 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> noted that pufferfish and human HARS proteins share 84% amino acid homology, suggesting a high degree of conservation. <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="#2" class="mim-tip-reference" title="Lo, W.-S., Gardiner, E., Xu, Z., Lau, C.-F., Wang, F., Zhou, J. J., Mendlein, J. D., Nangle, L. A., Chiang, K. P., Yang, X.-L., Au, K.-F., Wong, W. H., Guo, M., Zhang, M., Schimmel, P. <strong>Human tRNA synthetase catalytic nulls with diverse functions.</strong> Science 345: 328-332, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25035493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25035493</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25035493[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/10.1126/science.1252943" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25035493">Lo et al. (2014)</a> reported the discovery of a large number of natural catalytic nulls for each human aminoacyl tRNA synthetase. Splicing events retain noncatalytic domains while ablating the catalytic domain to create catalytic nulls with diverse functions. Each synthetase is converted into several new signaling proteins with biologic activities 'orthogonal' to that of the catalytic parent. The recombinant aminoacyl tRNA synthetase variants had specific biologic activities across a spectrum of cell-based assays: about 46% across all species affect transcriptional regulation, 22% cell differentiation, 10% immunomodulation, 10% cytoprotection, and 4% each for proliferation, adipogenesis/cholesterol transport, and inflammatory response. <a href="#2" class="mim-tip-reference" title="Lo, W.-S., Gardiner, E., Xu, Z., Lau, C.-F., Wang, F., Zhou, J. J., Mendlein, J. D., Nangle, L. A., Chiang, K. P., Yang, X.-L., Au, K.-F., Wong, W. H., Guo, M., Zhang, M., Schimmel, P. <strong>Human tRNA synthetase catalytic nulls with diverse functions.</strong> Science 345: 328-332, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25035493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25035493</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25035493[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/10.1126/science.1252943" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25035493">Lo et al. (2014)</a> identified in-frame splice variants of cytoplasmic aminoacyl tRNA synthetases. They identified 8 catalytic-null splice variants for HisRS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25035493" 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., 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 HARS gene contains 13 exons and spans approximately 17.4 kb. The HARS and HARS2 genes share a bidirectional promoter that lacks TATA and CAAT boxes. Both genes use multiple transcriptional start sites. HARS also uses a second, more distal promoter that overlaps the first exons of the HARS2 gene. <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><a href="#1" class="mim-tip-reference" title="Carlock, L. R., Skarecky, D., Dana, S. L., Wasmuth, J. J. <strong>Deletion mapping of human chromosome 5 using chromosome-specific DNA probes.</strong> Am. J. Hum. Genet. 37: 839-852, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2996334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2996334</a>]" pmid="2996334">Carlock et al. (1985)</a> used a Chinese hamster ovary (CHO) cell line with mutations in 3 genes, HARS, RPS14 (<a href="/entry/130620">130620</a>) and CHR (<a href="/entry/118840">118840</a>), in interspecies cell hybridization experiments, to assign the HARS gene to chromosome 5. <a href="#10" class="mim-tip-reference" title="Wasmuth, J. J., Carlock, L. R. <strong>Chromosomal localization of human gene for histidyl-tRNA synthetase: clustering of genes encoding aminoacyl-tRNA synthetases on human chromosome 5.</strong> Somat. Cell Molec. Genet. 12: 513-517, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3464104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3464104</a>] [<a href="https://doi.org/10.1007/BF01539922" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3464104">Wasmuth and Carlock (1986)</a> assigned the HARS gene to chromosome 5 by use of human-Chinese hamster ovary cell hybrids. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2996334+3464104" 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 genomic sequence analysis, <a href="#3" 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. HARS and HARS2 exhibit a head-to-head orientation, with 344 bp separating their ORFs. <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><strong><em>Usher Syndrome Type III</em></strong></p><p>
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In 2 patients from Old Order Amish families in Pennsylvania with Usher syndrome type III mapping to chromosome 5q (USH3B; <a href="/entry/614504">614504</a>), <a href="#5" class="mim-tip-reference" title="Puffenberger, E. G., Jinks, R. N., Sougnez, C., Cibulskis, K., Willert, R. A., Achilly, N. P., Cassidy, R. P., Fiorentini, C. J., Heiken, K. F., Lawrence, J. J., Mahoney, M. H., Miller, C. J., and 13 others. <strong>Genetic mapping and exome sequencing identify variants associated with five novel diseases.</strong> PLoS One 7: e28936, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22279524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22279524</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22279524[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/10.1371/journal.pone.0028936" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22279524">Puffenberger et al. (2012)</a> identified homozygosity for a missense mutation in the HARS gene (Y454S; <a href="#0001">142810.0001</a>) that was not found in dbSNP 129 or the 1000 Genomes Project. In addition, an Old Order Amish patient from an unrelated deme in Ontario, Canada, had an identical phenotype and was homozygous for the same mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22279524" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Charcot-Marie-Tooth Disease Type 2W</em></strong></p><p>
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In a 64-year-old man with a 15-year history of impaired sensation in the lower extremities and electrophysiologic studies consistent with axonal Charcot-Marie-Tooth disease type 2W (CMT2W; <a href="/entry/616625">616625</a>), <a href="#9" class="mim-tip-reference" title="Vester, A., Velez-Ruiz, G., McLaughlin, H. M., NISC Comparative Sequencing Program, Lupski, J. R., Talbot, K., Vance, J. M., Zuchner, S., Roda, R. H., Fischbeck, K. H., Biesecker, L. G., Nicholson, G., Beg, A. A., Antonellis, A. <strong>A loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo.</strong> Hum. Mutat. 34: 191-199, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22930593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22930593</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22930593[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.22210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22930593">Vester et al. (2013)</a> identified a heterozygous missense mutation in the HARS gene (R137Q; <a href="#0002">142810.0002</a>). The patient was ascertained from a larger cohort of 363 individuals with peripheral neuropathy. Generation of a yeast strain with deletion of the Hts1 gene (the ortholog of HARS) showed that the R137Q variant could not complement the Hts1 deletion, suggesting that it is a loss-of-function allele. Expression of the R137Q variant specifically in GABA motor nerves of C. elegans caused gross morphologic defects in commissural axons, with failure to reach the dorsal nerve cord, axonal beading, defasciculation, and breaks in the nerve cord. The animals with the variant also showed locomotor defects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22930593" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of 4 unrelated families with CMT2W, <a href="#7" class="mim-tip-reference" title="Safka Brozkova, D., Deconinck, T., Griffin, L. B., Ferbert, A., Haberlova, J., Mazanec, R., Lassuthova, P., Roth, C., Pilunthanakul, T., Rautenstrauss, B., Janecke, A. R., Zavadakova, P., and 9 others. <strong>Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies.</strong> Brain 138: 2161-2172, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26072516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26072516</a>] [<a href="https://doi.org/10.1093/brain/awv158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26072516">Safka Brozkova et al. (2015)</a> identified 4 different heterozygous missense mutations in the HARS gene (<a href="#0003">142810.0003</a>-<a href="#0006">142810.0006</a>). The mutations, which were found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the families. All mutations caused a loss of function in yeast complementation assays, and 1 of the mutations was dominantly neurotoxic in a C. elegans model. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26072516" 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>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>6 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=142810[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> rs387906639 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906639;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/rs387906639?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=rs387906639" 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=rs387906639" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 patients from Old Order Amish families in Pennsylvania with Usher syndrome type IIIB (USH3B; <a href="/entry/614504">614504</a>), <a href="#5" class="mim-tip-reference" title="Puffenberger, E. G., Jinks, R. N., Sougnez, C., Cibulskis, K., Willert, R. A., Achilly, N. P., Cassidy, R. P., Fiorentini, C. J., Heiken, K. F., Lawrence, J. J., Mahoney, M. H., Miller, C. J., and 13 others. <strong>Genetic mapping and exome sequencing identify variants associated with five novel diseases.</strong> PLoS One 7: e28936, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22279524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22279524</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22279524[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/10.1371/journal.pone.0028936" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22279524">Puffenberger et al. (2012)</a> identified homozygosity for a 1361A-C transversion in the HARS gene, resulting in a tyr454-to-ser (Y454S) substitution in the interface between the catalytic domain and the anticodon binding domain. A patient with an identical phenotype from an unrelated Old Order Amish deme in Ontario, Canada, was also homozygous for the Y454S mutation. The variant was not found in the dbSNP (build 129) or the 1000 Genomes Project databases; however, it was detected in 7 of 406 Old Order Amish alleles, for a population-specific allele frequency of 1.72%. (<a href="#6" class="mim-tip-reference" title="Puffenberger, E. G. <strong>Personal Communication.</strong> Strasburg, Pa. 2/28/2012."None>Puffenberger (2012)</a> stated that the correct population-specific allele frequency data appear in Table 4; corresponding data in the text are incorrect.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22279524" 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> rs191391414 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs191391414;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/rs191391414?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=rs191391414" 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=rs191391414" 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=RCV000033152 OR RCV000514458 OR RCV000650143 OR RCV002247415" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000033152, RCV000514458, RCV000650143, RCV002247415" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000033152...</a>
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<p>In a 64-year-old man with a 15-year history of impaired sensation in the lower extremities and electrophysiologic studies consistent with axonal Charcot-Marie-Tooth disease type 2W (CMT2W; <a href="/entry/616625">616625</a>), <a href="#9" class="mim-tip-reference" title="Vester, A., Velez-Ruiz, G., McLaughlin, H. M., NISC Comparative Sequencing Program, Lupski, J. R., Talbot, K., Vance, J. M., Zuchner, S., Roda, R. H., Fischbeck, K. H., Biesecker, L. G., Nicholson, G., Beg, A. A., Antonellis, A. <strong>A loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo.</strong> Hum. Mutat. 34: 191-199, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22930593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22930593</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22930593[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.22210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22930593">Vester et al. (2013)</a> identified a heterozygous 410G-A transition (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs191391414;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs191391414</a>) in the HARS gene, resulting in an arg137-to-gln (R137Q) substitution at a highly conserved residue in the catalytic core of the enzyme. The patient was ascertained from a larger cohort of 363 individuals with peripheral neuropathy. The R137Q variant was also found in 3 of over 13,000 control chromosomes. One of the control carriers had no evidence of neuropathy at age 57 years. Generation of a yeast strain with deletion of the Hts1 gene (the ortholog of HARS) showed that the R137Q variant could not complement the Hts1 deletion, suggesting that it is a loss-of-function allele. Expression of the R137Q variant specifically in GABA motor nerves of C. elegans caused gross morphologic defects in commissural axons, with failure to reach the dorsal nerve cord, axonal beading, defasciculation, and breaks in the nerve cord. The animals with the variant also showed locomotor defects. <a href="#9" class="mim-tip-reference" title="Vester, A., Velez-Ruiz, G., McLaughlin, H. M., NISC Comparative Sequencing Program, Lupski, J. R., Talbot, K., Vance, J. M., Zuchner, S., Roda, R. H., Fischbeck, K. H., Biesecker, L. G., Nicholson, G., Beg, A. A., Antonellis, A. <strong>A loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo.</strong> Hum. Mutat. 34: 191-199, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22930593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22930593</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22930593[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.22210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22930593">Vester et al. (2013)</a> concluded that the HARS R137Q variant may be a pathogenic allele that predisposes to the development of peripheral neuropathy, similar to other ARS mutations (see, e.g., GARS, <a href="/entry/600287">600287</a>), but noted that a causal link remains unclear. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22930593" 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 large multigenerational family (family A) with Charcot-Marie-Tooth disease type 2W (CMT2W; <a href="/entry/616625">616625</a>), <a href="#7" class="mim-tip-reference" title="Safka Brozkova, D., Deconinck, T., Griffin, L. B., Ferbert, A., Haberlova, J., Mazanec, R., Lassuthova, P., Roth, C., Pilunthanakul, T., Rautenstrauss, B., Janecke, A. R., Zavadakova, P., and 9 others. <strong>Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies.</strong> Brain 138: 2161-2172, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26072516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26072516</a>] [<a href="https://doi.org/10.1093/brain/awv158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26072516">Safka Brozkova et al. (2015)</a> identified a heterozygous c.395C-T transition in the HARS gene, resulting in a thr132-to-ile (T132I) substitution. The mutation, which was found by linkage analysis and candidate gene sequencing, segregated with the disorder in the family and was not found in the dbSNP, Exome Variant Server, or 1000 Genomes Project databases. In vitro studies showed that the mutation was unable to rescue a growth defect in yeast depleted of the ortholog Hts1, consistent with a complete loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26072516" 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>.0004 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2W</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs863225122 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863225122;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs863225122" 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=rs863225122" 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=RCV000201516" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000201516" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000201516</a>
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<p>In affected members of a family (family B) with autosomal dominant Charcot-Marie-Tooth disease type 2W (CMT2W; <a href="/entry/616625">616625</a>), <a href="#7" class="mim-tip-reference" title="Safka Brozkova, D., Deconinck, T., Griffin, L. B., Ferbert, A., Haberlova, J., Mazanec, R., Lassuthova, P., Roth, C., Pilunthanakul, T., Rautenstrauss, B., Janecke, A. R., Zavadakova, P., and 9 others. <strong>Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies.</strong> Brain 138: 2161-2172, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26072516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26072516</a>] [<a href="https://doi.org/10.1093/brain/awv158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26072516">Safka Brozkova et al. (2015)</a> identified a heterozygous c.401C-A transversion in the HARS gene, resulting in a pro134-to-his (P134H) substitution. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP, Exome Variant Server, or 1000 Genomes Project databases. In vitro studies showed that the mutation was unable to rescue a growth defect in yeast depleted of the ortholog Hts1, consistent with a complete loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26072516" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2W</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs863225123 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863225123;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs863225123" 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=rs863225123" 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=RCV000201520" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000201520" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000201520</a>
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<p>In affected members of a 3-generation family (family C) with autosomal dominant Charcot-Marie-Tooth disease type 2W (CMT2W; <a href="/entry/616625">616625</a>), <a href="#7" class="mim-tip-reference" title="Safka Brozkova, D., Deconinck, T., Griffin, L. B., Ferbert, A., Haberlova, J., Mazanec, R., Lassuthova, P., Roth, C., Pilunthanakul, T., Rautenstrauss, B., Janecke, A. R., Zavadakova, P., and 9 others. <strong>Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies.</strong> Brain 138: 2161-2172, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26072516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26072516</a>] [<a href="https://doi.org/10.1093/brain/awv158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26072516">Safka Brozkova et al. (2015)</a> identified a heterozygous c.525T-G transversion in the HARS gene, resulting in an asp175-to-glu (D175E) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP, Exome Variant Server, or 1000 Genomes Project databases. In vitro studies showed that the mutation was only partially able to rescue a growth defect in yeast depleted of the ortholog Hts1, consistent with a partial loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26072516" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2W</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs863225124 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863225124;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs863225124" 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=rs863225124" 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=RCV000201523" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000201523" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000201523</a>
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<p>In affected members of a multigenerational family (family D) with autosomal dominant Charcot-Marie-Tooth disease type 2W (CMT2W; <a href="/entry/616625">616625</a>), <a href="#7" class="mim-tip-reference" title="Safka Brozkova, D., Deconinck, T., Griffin, L. B., Ferbert, A., Haberlova, J., Mazanec, R., Lassuthova, P., Roth, C., Pilunthanakul, T., Rautenstrauss, B., Janecke, A. R., Zavadakova, P., and 9 others. <strong>Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies.</strong> Brain 138: 2161-2172, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26072516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26072516</a>] [<a href="https://doi.org/10.1093/brain/awv158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26072516">Safka Brozkova et al. (2015)</a> identified a heterozygous c.1090G-T transversion in the HARS gene, resulting in an asp364-to-tyr (D364Y) substitution. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP, Exome Variant Server, or 1000 Genomes Project databases. In vitro studies showed that the mutation was unable to rescue a growth defect in yeast depleted of the ortholog Hts1, consistent with a complete loss of function. Expression of the D364Y mutation in C. elegans resulted in morphologic neurotoxicity, including dorsal and ventral nerve gaps, axonal blebbing, and severely aberrant axonal processes. Animals with the mutation also showed progressively impaired locomotor performance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26072516" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Tsui1985" class="mim-tip-reference" title="Tsui, F. W. L., Andrulis, I. L., Murialdo, H., Siminovitch, L. <strong>Amplification of the gene for histidyl-tRNA synthetase in histidinol-resistant Chinese hamster ovary cells.</strong> Molec. Cell. Biol. 5: 2381-2388, 1985.">Tsui et al. (1985)</a>
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Carlock, L. R., Skarecky, D., Dana, S. L., Wasmuth, J. J.
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<strong>Deletion mapping of human chromosome 5 using chromosome-specific DNA probes.</strong>
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Am. J. Hum. Genet. 37: 839-852, 1985.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2996334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2996334</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2996334" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Lo, W.-S., Gardiner, E., Xu, Z., Lau, C.-F., Wang, F., Zhou, J. J., Mendlein, J. D., Nangle, L. A., Chiang, K. P., Yang, X.-L., Au, K.-F., Wong, W. H., Guo, M., Zhang, M., Schimmel, P.
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<strong>Human tRNA synthetase catalytic nulls with diverse functions.</strong>
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Science 345: 328-332, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25035493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25035493</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25035493[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=25035493" 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/10.1126/science.1252943" target="_blank">Full Text</a>]
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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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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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Puffenberger, E. G., Jinks, R. N., Sougnez, C., Cibulskis, K., Willert, R. A., Achilly, N. P., Cassidy, R. P., Fiorentini, C. J., Heiken, K. F., Lawrence, J. J., Mahoney, M. H., Miller, C. J., and 13 others.
|
|
<strong>Genetic mapping and exome sequencing identify variants associated with five novel diseases.</strong>
|
|
PLoS One 7: e28936, 2012. Note: Electronic Article.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22279524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22279524</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22279524[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=22279524" 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/10.1371/journal.pone.0028936" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="6" class="mim-anchor"></a>
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<a id="Puffenberger2012" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
|
|
Puffenberger, E. G.
|
|
<strong>Personal Communication.</strong>
|
|
Strasburg, Pa. 2/28/2012.
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</p>
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</div>
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</li>
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<li>
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<a id="7" class="mim-anchor"></a>
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<a id="Safka Brozkova2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Safka Brozkova, D., Deconinck, T., Griffin, L. B., Ferbert, A., Haberlova, J., Mazanec, R., Lassuthova, P., Roth, C., Pilunthanakul, T., Rautenstrauss, B., Janecke, A. R., Zavadakova, P., and 9 others.
|
|
<strong>Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies.</strong>
|
|
Brain 138: 2161-2172, 2015.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26072516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26072516</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26072516" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/awv158" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="8" class="mim-anchor"></a>
|
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<a id="Tsui1985" class="mim-anchor"></a>
|
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<div class="">
|
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<p class="mim-text-font">
|
|
Tsui, F. W. L., Andrulis, I. L., Murialdo, H., Siminovitch, L.
|
|
<strong>Amplification of the gene for histidyl-tRNA synthetase in histidinol-resistant Chinese hamster ovary cells.</strong>
|
|
Molec. Cell. Biol. 5: 2381-2388, 1985.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2874482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2874482</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2874482" 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/10.1128/mcb.5.9.2381-2388.1985" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="9" class="mim-anchor"></a>
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<a id="Vester2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
|
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Vester, A., Velez-Ruiz, G., McLaughlin, H. M., NISC Comparative Sequencing Program, Lupski, J. R., Talbot, K., Vance, J. M., Zuchner, S., Roda, R. H., Fischbeck, K. H., Biesecker, L. G., Nicholson, G., Beg, A. A., Antonellis, A.
|
|
<strong>A loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo.</strong>
|
|
Hum. Mutat. 34: 191-199, 2013.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22930593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22930593</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22930593[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=22930593" 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/humu.22210" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="10" class="mim-anchor"></a>
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<a id="Wasmuth1986" class="mim-anchor"></a>
|
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<div class="">
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<p class="mim-text-font">
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Wasmuth, J. J., Carlock, L. R.
|
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<strong>Chromosomal localization of human gene for histidyl-tRNA synthetase: clustering of genes encoding aminoacyl-tRNA synthetases on human chromosome 5.</strong>
|
|
Somat. Cell Molec. Genet. 12: 513-517, 1986.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3464104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3464104</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3464104" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/BF01539922" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
Cassandra L. Kniffin - updated : 11/2/2015
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</span>
|
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</div>
|
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</div>
|
|
<div class="row collapse" id="mimCollapseContributors">
|
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
Ada Hamosh - updated : 8/29/2014<br>Cassandra L. Kniffin - updated : 2/19/2013<br>Marla J. F. O'Neill - updated : 2/28/2012<br>Patricia A. Hartz - updated : 9/11/2009
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
|
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<div class="row">
|
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
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<span class="text-nowrap mim-text-font">
|
|
Creation Date:
|
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</span>
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</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Victor A. McKusick : 6/4/1986
|
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
|
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
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<span class="text-nowrap mim-text-font">
|
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
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</span>
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</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
carol : 08/20/2019
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</span>
|
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</div>
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</div>
|
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<div class="row collapse" id="mimCollapseEditHistory">
|
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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|
carol : 06/14/2018<br>joanna : 11/14/2017<br>alopez : 11/03/2015<br>ckniffin : 11/2/2015<br>alopez : 8/29/2014<br>carol : 7/26/2013<br>carol : 2/20/2013<br>carol : 2/20/2013<br>ckniffin : 2/19/2013<br>terry : 2/29/2012<br>carol : 2/29/2012<br>carol : 2/28/2012<br>mgross : 9/15/2009<br>terry : 9/11/2009<br>terry : 9/19/1995<br>supermim : 3/16/1992<br>supermim : 3/20/1990<br>ddp : 10/27/1989<br>marie : 3/25/1988<br>marie : 12/15/1986
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
|
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<h3>
|
|
<span class="mim-font">
|
|
<strong>*</strong> 142810
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
HISTIDYL-tRNA SYNTHETASE 1; HARS1
|
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|
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</span>
|
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</h3>
|
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</div>
|
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
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</span>
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</p>
|
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</div>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
HARS<br />
|
|
HRS<br />
|
|
HISRS
|
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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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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: HARS1</em></strong>
|
|
</span>
|
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</p>
|
|
</div>
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<div>
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<p>
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|
<span class="mim-text-font">
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|
|
|
<strong>SNOMEDCT:</strong> 1172634009;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
|
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<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: 5q31.3
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 5:140,673,905-140,691,370 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
5q31.3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Charcot-Marie-Tooth disease, axonal, type 2W
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
616625
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
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|
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</tr>
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|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Usher syndrome type 3B
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
614504
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
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</tbody>
|
|
</table>
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</div>
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|
</div>
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<div>
|
|
<br />
|
|
</div>
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<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>HARS catalyzes the covalent ligation of histidine to its cognate tRNA as an early step in protein biosynthesis (O'Hanlon and Miller, 2002). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>O'Hanlon et al. (1995) noted that HARS and HARS2 (600783), which they called HO3, are oriented in a head-to-head configuration and share a bidirectional promoter. They reported that the deduced 509-amino acid HARS protein shares 72% amino acid identity with HARS2. 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. HARS has a calculated molecular mass of 57.4 kD. Northern blot analysis detected a 2.0-kb HARS transcript that was highly expressed in heart, brain, liver, and kidney. </p><p>Using 5-prime RACE with a human kidney cDNA library, O'Hanlon and Miller (2002) identified several HARS transcripts that differed only in the lengths of their 5-prime UTRs. O'Hanlon and Miller (2002) noted that pufferfish and human HARS proteins share 84% amino acid homology, suggesting a high degree of conservation. </p><p>Lo et al. (2014) reported the discovery of a large number of natural catalytic nulls for each human aminoacyl tRNA synthetase. Splicing events retain noncatalytic domains while ablating the catalytic domain to create catalytic nulls with diverse functions. Each synthetase is converted into several new signaling proteins with biologic activities 'orthogonal' to that of the catalytic parent. The recombinant aminoacyl tRNA synthetase variants had specific biologic activities across a spectrum of cell-based assays: about 46% across all species affect transcriptional regulation, 22% cell differentiation, 10% immunomodulation, 10% cytoprotection, and 4% each for proliferation, adipogenesis/cholesterol transport, and inflammatory response. Lo et al. (2014) identified in-frame splice variants of cytoplasmic aminoacyl tRNA synthetases. They identified 8 catalytic-null splice variants for HisRS. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>O'Hanlon and Miller (2002) determined that the HARS gene contains 13 exons and spans approximately 17.4 kb. The HARS and HARS2 genes share a bidirectional promoter that lacks TATA and CAAT boxes. Both genes use multiple transcriptional start sites. HARS also uses a second, more distal promoter that overlaps the first exons of the HARS2 gene. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<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>Carlock et al. (1985) used a Chinese hamster ovary (CHO) cell line with mutations in 3 genes, HARS, RPS14 (130620) and CHR (118840), in interspecies cell hybridization experiments, to assign the HARS gene to chromosome 5. Wasmuth and Carlock (1986) assigned the HARS gene to chromosome 5 by use of human-Chinese hamster ovary cell hybrids. </p><p>By genomic sequence analysis, O'Hanlon and Miller (2002) mapped the HARS and HARS2 genes to chromosome 5q31.3. HARS and HARS2 exhibit a head-to-head orientation, with 344 bp separating their ORFs. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Usher Syndrome Type III</em></strong></p><p>
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In 2 patients from Old Order Amish families in Pennsylvania with Usher syndrome type III mapping to chromosome 5q (USH3B; 614504), Puffenberger et al. (2012) identified homozygosity for a missense mutation in the HARS gene (Y454S; 142810.0001) that was not found in dbSNP 129 or the 1000 Genomes Project. In addition, an Old Order Amish patient from an unrelated deme in Ontario, Canada, had an identical phenotype and was homozygous for the same mutation. </p><p><strong><em>Charcot-Marie-Tooth Disease Type 2W</em></strong></p><p>
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In a 64-year-old man with a 15-year history of impaired sensation in the lower extremities and electrophysiologic studies consistent with axonal Charcot-Marie-Tooth disease type 2W (CMT2W; 616625), Vester et al. (2013) identified a heterozygous missense mutation in the HARS gene (R137Q; 142810.0002). The patient was ascertained from a larger cohort of 363 individuals with peripheral neuropathy. Generation of a yeast strain with deletion of the Hts1 gene (the ortholog of HARS) showed that the R137Q variant could not complement the Hts1 deletion, suggesting that it is a loss-of-function allele. Expression of the R137Q variant specifically in GABA motor nerves of C. elegans caused gross morphologic defects in commissural axons, with failure to reach the dorsal nerve cord, axonal beading, defasciculation, and breaks in the nerve cord. The animals with the variant also showed locomotor defects. </p><p>In affected members of 4 unrelated families with CMT2W, Safka Brozkova et al. (2015) identified 4 different heterozygous missense mutations in the HARS gene (142810.0003-142810.0006). The mutations, which were found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the families. All mutations caused a loss of function in yeast complementation assays, and 1 of the mutations was dominantly neurotoxic in a C. elegans model. </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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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>6 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 USHER SYNDROME, TYPE IIIB</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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HARS1, TYR454SER
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<br />
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SNP: rs387906639,
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gnomAD: rs387906639,
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ClinVar: RCV000022619, RCV000608744, RCV000623702
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 patients from Old Order Amish families in Pennsylvania with Usher syndrome type IIIB (USH3B; 614504), Puffenberger et al. (2012) identified homozygosity for a 1361A-C transversion in the HARS gene, resulting in a tyr454-to-ser (Y454S) substitution in the interface between the catalytic domain and the anticodon binding domain. A patient with an identical phenotype from an unrelated Old Order Amish deme in Ontario, Canada, was also homozygous for the Y454S mutation. The variant was not found in the dbSNP (build 129) or the 1000 Genomes Project databases; however, it was detected in 7 of 406 Old Order Amish alleles, for a population-specific allele frequency of 1.72%. (Puffenberger (2012) stated that the correct population-specific allele frequency data appear in Table 4; corresponding data in the text are incorrect.) </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 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2W</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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HARS1, ARG137GLN ({dbSNP rs191391414})
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<br />
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SNP: rs191391414,
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gnomAD: rs191391414,
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ClinVar: RCV000033152, RCV000514458, RCV000650143, RCV002247415
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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>In a 64-year-old man with a 15-year history of impaired sensation in the lower extremities and electrophysiologic studies consistent with axonal Charcot-Marie-Tooth disease type 2W (CMT2W; 616625), Vester et al. (2013) identified a heterozygous 410G-A transition (rs191391414) in the HARS gene, resulting in an arg137-to-gln (R137Q) substitution at a highly conserved residue in the catalytic core of the enzyme. The patient was ascertained from a larger cohort of 363 individuals with peripheral neuropathy. The R137Q variant was also found in 3 of over 13,000 control chromosomes. One of the control carriers had no evidence of neuropathy at age 57 years. Generation of a yeast strain with deletion of the Hts1 gene (the ortholog of HARS) showed that the R137Q variant could not complement the Hts1 deletion, suggesting that it is a loss-of-function allele. Expression of the R137Q variant specifically in GABA motor nerves of C. elegans caused gross morphologic defects in commissural axons, with failure to reach the dorsal nerve cord, axonal beading, defasciculation, and breaks in the nerve cord. The animals with the variant also showed locomotor defects. Vester et al. (2013) concluded that the HARS R137Q variant may be a pathogenic allele that predisposes to the development of peripheral neuropathy, similar to other ARS mutations (see, e.g., GARS, 600287), but noted that a causal link remains unclear. </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>.0003 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2W</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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HARS1, THR132ILE
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<br />
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SNP: rs143473232,
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gnomAD: rs143473232,
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ClinVar: RCV000201522, RCV001092021
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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>In affected members of a large multigenerational family (family A) with Charcot-Marie-Tooth disease type 2W (CMT2W; 616625), Safka Brozkova et al. (2015) identified a heterozygous c.395C-T transition in the HARS gene, resulting in a thr132-to-ile (T132I) substitution. The mutation, which was found by linkage analysis and candidate gene sequencing, segregated with the disorder in the family and was not found in the dbSNP, Exome Variant Server, or 1000 Genomes Project databases. In vitro studies showed that the mutation was unable to rescue a growth defect in yeast depleted of the ortholog Hts1, consistent with a complete loss of function. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
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|
</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2W</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
HARS1, PRO134HIS
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|
|
<br />
|
|
|
|
SNP: rs863225122,
|
|
|
|
|
|
|
|
ClinVar: RCV000201516
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family (family B) with autosomal dominant Charcot-Marie-Tooth disease type 2W (CMT2W; 616625), Safka Brozkova et al. (2015) identified a heterozygous c.401C-A transversion in the HARS gene, resulting in a pro134-to-his (P134H) substitution. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP, Exome Variant Server, or 1000 Genomes Project databases. In vitro studies showed that the mutation was unable to rescue a growth defect in yeast depleted of the ortholog Hts1, consistent with a complete loss of function. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2W</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HARS1, ASP175GLU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs863225123,
|
|
|
|
|
|
|
|
ClinVar: RCV000201520
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a 3-generation family (family C) with autosomal dominant Charcot-Marie-Tooth disease type 2W (CMT2W; 616625), Safka Brozkova et al. (2015) identified a heterozygous c.525T-G transversion in the HARS gene, resulting in an asp175-to-glu (D175E) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP, Exome Variant Server, or 1000 Genomes Project databases. In vitro studies showed that the mutation was only partially able to rescue a growth defect in yeast depleted of the ortholog Hts1, consistent with a partial loss of function. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2W</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HARS1, ASP364TYR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs863225124,
|
|
|
|
|
|
|
|
ClinVar: RCV000201523
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a multigenerational family (family D) with autosomal dominant Charcot-Marie-Tooth disease type 2W (CMT2W; 616625), Safka Brozkova et al. (2015) identified a heterozygous c.1090G-T transversion in the HARS gene, resulting in an asp364-to-tyr (D364Y) substitution. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP, Exome Variant Server, or 1000 Genomes Project databases. In vitro studies showed that the mutation was unable to rescue a growth defect in yeast depleted of the ortholog Hts1, consistent with a complete loss of function. Expression of the D364Y mutation in C. elegans resulted in morphologic neurotoxicity, including dorsal and ventral nerve gaps, axonal blebbing, and severely aberrant axonal processes. Animals with the mutation also showed progressively impaired locomotor performance. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
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|
|
</div>
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<span class="mim-text-font">
|
|
Tsui et al. (1985)
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
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|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
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|
<li>
|
|
<p class="mim-text-font">
|
|
Carlock, L. R., Skarecky, D., Dana, S. L., Wasmuth, J. J.
|
|
<strong>Deletion mapping of human chromosome 5 using chromosome-specific DNA probes.</strong>
|
|
Am. J. Hum. Genet. 37: 839-852, 1985.
|
|
|
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|
|
[PubMed: 2996334]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Lo, W.-S., Gardiner, E., Xu, Z., Lau, C.-F., Wang, F., Zhou, J. J., Mendlein, J. D., Nangle, L. A., Chiang, K. P., Yang, X.-L., Au, K.-F., Wong, W. H., Guo, M., Zhang, M., Schimmel, P.
|
|
<strong>Human tRNA synthetase catalytic nulls with diverse functions.</strong>
|
|
Science 345: 328-332, 2014.
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|
|
[PubMed: 25035493]
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[Full Text: https://doi.org/10.1126/science.1252943]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
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.
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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>
|
|
<p class="mim-text-font">
|
|
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.
|
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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">
|
|
Puffenberger, E. G., Jinks, R. N., Sougnez, C., Cibulskis, K., Willert, R. A., Achilly, N. P., Cassidy, R. P., Fiorentini, C. J., Heiken, K. F., Lawrence, J. J., Mahoney, M. H., Miller, C. J., and 13 others.
|
|
<strong>Genetic mapping and exome sequencing identify variants associated with five novel diseases.</strong>
|
|
PLoS One 7: e28936, 2012. Note: Electronic Article.
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[PubMed: 22279524]
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[Full Text: https://doi.org/10.1371/journal.pone.0028936]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Puffenberger, E. G.
|
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<strong>Personal Communication.</strong>
|
|
Strasburg, Pa. 2/28/2012.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Safka Brozkova, D., Deconinck, T., Griffin, L. B., Ferbert, A., Haberlova, J., Mazanec, R., Lassuthova, P., Roth, C., Pilunthanakul, T., Rautenstrauss, B., Janecke, A. R., Zavadakova, P., and 9 others.
|
|
<strong>Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies.</strong>
|
|
Brain 138: 2161-2172, 2015.
|
|
|
|
|
|
[PubMed: 26072516]
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[Full Text: https://doi.org/10.1093/brain/awv158]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Tsui, F. W. L., Andrulis, I. L., Murialdo, H., Siminovitch, L.
|
|
<strong>Amplification of the gene for histidyl-tRNA synthetase in histidinol-resistant Chinese hamster ovary cells.</strong>
|
|
Molec. Cell. Biol. 5: 2381-2388, 1985.
|
|
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|
|
|
[PubMed: 2874482]
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|
|
[Full Text: https://doi.org/10.1128/mcb.5.9.2381-2388.1985]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Vester, A., Velez-Ruiz, G., McLaughlin, H. M., NISC Comparative Sequencing Program, Lupski, J. R., Talbot, K., Vance, J. M., Zuchner, S., Roda, R. H., Fischbeck, K. H., Biesecker, L. G., Nicholson, G., Beg, A. A., Antonellis, A.
|
|
<strong>A loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo.</strong>
|
|
Hum. Mutat. 34: 191-199, 2013.
|
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|
[PubMed: 22930593]
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[Full Text: https://doi.org/10.1002/humu.22210]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Wasmuth, J. J., Carlock, L. R.
|
|
<strong>Chromosomal localization of human gene for histidyl-tRNA synthetase: clustering of genes encoding aminoacyl-tRNA synthetases on human chromosome 5.</strong>
|
|
Somat. Cell Molec. Genet. 12: 513-517, 1986.
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|
[PubMed: 3464104]
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[Full Text: https://doi.org/10.1007/BF01539922]
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Cassandra L. Kniffin - updated : 11/2/2015<br>Ada Hamosh - updated : 8/29/2014<br>Cassandra L. Kniffin - updated : 2/19/2013<br>Marla J. F. O'Neill - updated : 2/28/2012<br>Patricia A. Hartz - updated : 9/11/2009
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Victor A. McKusick : 6/4/1986
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carol : 08/20/2019<br>carol : 06/14/2018<br>joanna : 11/14/2017<br>alopez : 11/03/2015<br>ckniffin : 11/2/2015<br>alopez : 8/29/2014<br>carol : 7/26/2013<br>carol : 2/20/2013<br>carol : 2/20/2013<br>ckniffin : 2/19/2013<br>terry : 2/29/2012<br>carol : 2/29/2012<br>carol : 2/28/2012<br>mgross : 9/15/2009<br>terry : 9/11/2009<br>terry : 9/19/1995<br>supermim : 3/16/1992<br>supermim : 3/20/1990<br>ddp : 10/27/1989<br>marie : 3/25/1988<br>marie : 12/15/1986
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