3186 lines
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Entry
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- *108410 - ASPARAGINYL-tRNA SYNTHETASE 1; NARS1
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*108410</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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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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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 role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/108410">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000134440;t=ENST00000256854" 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=4677" 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=108410" 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=ENSG00000134440;t=ENST00000256854" 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_004539,XM_005266700" 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_004539" 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=108410" 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=00154&isoform_id=00154_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/NARS1" 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/2764505,3894218,3915059,4758762,12804549,62897229,119583452,119583453,194376016,194377358,194378294,194387516,530414204,2462560536" 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/O43776" 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=4677" 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=ENSG00000134440;t=ENST00000256854" 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=NARS1" 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=NARS1" 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+4677" 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/NARS1" 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:4677" 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/4677" 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=chr18&hgg_gene=ENST00000256854.10&hgg_start=57600656&hgg_end=57621836&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:7643" 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=108410[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=108410[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/NARS1/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000134440" 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=NARS1" 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=NARS1" 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=NARS1" 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=NARS1&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/PA31447" 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:7643" 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/FBgn0086443.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:1917473" 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/NARS1#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:1917473" 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/4677/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=4677" 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=WBGene00003815;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-030131-1016" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:4677" 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=NARS1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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108410
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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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ASPARAGINYL-tRNA SYNTHETASE 1; NARS1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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NARS<br />
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ASNRS
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=NARS1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">NARS1</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
|
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<strong>
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<em>
|
|
Cytogenetic location: <a href="/geneMap/18/207?start=-3&limit=10&highlight=207">18q21.31</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr18:57600656-57621836&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'})">18:57,600,656-57,621,836</a> </span>
|
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</em>
|
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</div>
|
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
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Location
|
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</th>
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<th>
|
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Phenotype
|
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=619091,619092" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
|
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</th>
|
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<th>
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|
Phenotype <br /> MIM number
|
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</th>
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<th>
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Inheritance
|
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</th>
|
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<th>
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Phenotype <br /> mapping key
|
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</th>
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</tr>
|
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</thead>
|
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<tbody>
|
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<tr>
|
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<td rowspan="2">
|
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<span class="mim-font">
|
|
<a href="/geneMap/18/207?start=-3&limit=10&highlight=207">
|
|
18q21.31
|
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</a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/619091"> 619091 </a>
|
|
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<tr>
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<td>
|
|
<span class="mim-font">
|
|
Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/619092"> 619092 </a>
|
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|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
|
|
</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/108410" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/108410" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
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<p>The NARS1 gene encodes the cytoplasmic asparaginyl-tRNA synthetase that mediates the charging of the Asn amino acid onto its cognate transfer RNA, which is essential for protein synthesis (summary by <a href="#6" class="mim-tip-reference" title="Wang, L., Li, Z., Sievert, D., Smith, D. E. C., Mendes, M. I., Chen, D. Y., Stanley, V., Ghosh, S., Wang, Y., Kara, M., Aslanger, A. D., Rosti, R. O., Houlden, H., Salomons, G. S., Gleeson, J. G. <strong>Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly.</strong> Nature Commun. 11: 4038, 2020. Note: Electronic Article. Erratum: Nature Commun. 12: 1192, 2021. Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32788587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32788587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32788587[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/10.1038/s41467-020-17454-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32788587">Wang et al., 2020</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32788587" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#2" class="mim-tip-reference" title="Cirullo, R. E., Arredondo-Vega, F. X., Smith, M., Wasmuth, J. J. <strong>Isolation and characterization of interspecific heat-resistant hybrids between a temperature-sensitive Chinese hamster cell asparaginyl-tRNA synthetase mutant and normal human leukocytes: assignment of human asnS gene to chromosome 18.</strong> Somat. Cell Genet. 9: 215-233, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6836455/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6836455</a>] [<a href="https://doi.org/10.1007/BF01543178" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6836455">Cirullo et al. (1983)</a> isolated hybrids between human peripheral leukocytes and a temperature-sensitive CHO cell line with a thermolabile asparaginyl-tRNA synthetase (<a href="https://enzyme.expasy.org/EC/6.1.1.22" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 6.1.1.22</a>), which they symbolized 'asnS.' Hybrids selected at 39 degrees C required the presence of human chromosome 18. Temperature-resistant hybrid cells contained 2 forms of ASNRS: 1 highly thermal resistant, like the human enzyme, and 1 highly thermolabile, like the CHO mutant enzyme. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6836455" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Beaulande, M., Tarbouriech, N., Hartlein, M. <strong>Human cytosolic asparaginyl-tRNA synthetase: cDNA sequence, functional expression in Escherichia coli and characterization as human autoantigen.</strong> Nucleic Acids Res. 26: 521-524, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9421509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9421509</a>] [<a href="https://doi.org/10.1093/nar/26.2.521" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9421509">Beaulande et al. (1998)</a> cloned a human cytosolic ASNRS cDNA from a liver cDNA library. The deduced 548-amino acid protein has a predicted molecular mass of 62.9 kD and shares 53% sequence identity with the S. cerevisiae homolog. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9421509" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="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="#3" 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 1 catalytic-null splice variant for AsnRS. <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>Using a DNA probe in human-rodent hybrid cells, <a href="#5" class="mim-tip-reference" title="Shows, T. B. <strong>Personal Communication.</strong> Buffalo, N. Y. 1/11/1983."None>Shows (1983)</a> found that asparaginyl-tRNA synthetase segregated with peptidase A, a chromosome 18 marker.</p>
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<p>By Western blot analysis, <a href="#1" class="mim-tip-reference" title="Beaulande, M., Tarbouriech, N., Hartlein, M. <strong>Human cytosolic asparaginyl-tRNA synthetase: cDNA sequence, functional expression in Escherichia coli and characterization as human autoantigen.</strong> Nucleic Acids Res. 26: 521-524, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9421509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9421509</a>] [<a href="https://doi.org/10.1093/nar/26.2.521" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9421509">Beaulande et al. (1998)</a> showed that a human autoimmune serum (anti-KS) neutralized human AsnRSc activity, suggesting that it is a class II aminoacyl-tRNA synthetase involved in autoimmune reactions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9421509" 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>Neurodevelopmental Disorder with Microcephaly, Impaired Language, and Gait Abnormalities</em></strong></p><p>
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In 23 patients from 13 unrelated families with neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG; <a href="/entry/619091">619091</a>), <a href="#6" class="mim-tip-reference" title="Wang, L., Li, Z., Sievert, D., Smith, D. E. C., Mendes, M. I., Chen, D. Y., Stanley, V., Ghosh, S., Wang, Y., Kara, M., Aslanger, A. D., Rosti, R. O., Houlden, H., Salomons, G. S., Gleeson, J. G. <strong>Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly.</strong> Nature Commun. 11: 4038, 2020. Note: Electronic Article. Erratum: Nature Commun. 12: 1192, 2021. Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32788587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32788587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32788587[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/10.1038/s41467-020-17454-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32788587">Wang et al. (2020)</a> and <a href="#4" class="mim-tip-reference" title="Manole, A., Efthymiou, S., O'Connor, E., Mendes, M. I., Jennings, M., Maroofian, R., Davagnanam, I., Mankad, K., Lopez, M. R., Salpietro, V., Harripaul, R., Badalato, L., and 81 others. <strong>De novo and bi-allelic pathogenic variants in NARS1 cause neurodevelopmental delay due to toxic gain-of-function and partial loss-of-function effects.</strong> Am. J. Hum. Genet. 107: 311-324, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32738225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32738225</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32738225[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.06.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32738225">Manole et al. (2020)</a> identified homozygous or compound heterozygous mutations in the NARS1 gene (see, e.g., <a href="#0001">108410.0001</a>-<a href="#0005">108410.0005</a>). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Most of the mutations were missense, although 2 families carried a nonsense or frameshift mutation on 1 allele. Affected members of 7 consanguineous families (families 9-15) carried the same homozygous R545C mutation (<a href="#0004">108410.0004</a>). Fibroblasts derived from 3 unrelated patients showed variably decreased NARS1 protein levels, impaired homodimerization, reduced cytoplasmic transferase activity, and decreased global protein synthesis compared to controls. These findings suggested that the mutations resulted in a loss of function. Induced neuronal progenitor cells derived from 2 unrelated patients were used to generate cultures of 3D cortical brain organoids (CO). Mutant organoids became progressively smaller with decreased diameter compared to controls beginning around division 52, modeling the microcephaly observed in the patients. Patient CO showed reduced generation of radial glial cells with abnormal neural rosette structure, depletion of rosettes and postmitotic neurons, and decreased proliferation and viability of progenitor cells compared to wildtype. RNA-seq analysis of patient cells detected abnormalities in cell cycle control and neuronal progenitor cell fate differentiation, suggesting a role for NARS1 in these processes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=32738225+32788587" 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>Neurodevelopmental Disorder with Microcephaly, Impaired Language, Epilepsy, and Gait Abnormalities</em></strong></p><p>
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In 6 unrelated patients (patients 1-6) with neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG; <a href="/entry/619092">619092</a>), <a href="#4" class="mim-tip-reference" title="Manole, A., Efthymiou, S., O'Connor, E., Mendes, M. I., Jennings, M., Maroofian, R., Davagnanam, I., Mankad, K., Lopez, M. R., Salpietro, V., Harripaul, R., Badalato, L., and 81 others. <strong>De novo and bi-allelic pathogenic variants in NARS1 cause neurodevelopmental delay due to toxic gain-of-function and partial loss-of-function effects.</strong> Am. J. Hum. Genet. 107: 311-324, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32738225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32738225</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32738225[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.06.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32738225">Manole et al. (2020)</a> identified a de novo heterozygous nonsense mutation in the NARS1 gene (R534X; <a href="#0006">108410.0006</a>). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Cells derived from 1 patient showed a dramatic decrease in enzyme activity compared to wildtype. Expression of this mutation in zebrafish caused cyclopia and gastrulation defects. The authors postulated a toxic gain-of-function dominant-negative effect. Two additional patients (patients 7 and 8) with a similar disorder but without microcephaly carried de novo heterozygous missense variants in the NARS1 gene (G509S and R322L) that were not present in the gnomAD database. Functional studies of these variants were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32738225" 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> rs148893823 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs148893823;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/rs148893823?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=rs148893823" 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=rs148893823" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In an 8-year-old girl, born of consanguineous parents from Libya (family MIC-1433, family 17), with neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG; <a href="/entry/619091">619091</a>), <a href="#6" class="mim-tip-reference" title="Wang, L., Li, Z., Sievert, D., Smith, D. E. C., Mendes, M. I., Chen, D. Y., Stanley, V., Ghosh, S., Wang, Y., Kara, M., Aslanger, A. D., Rosti, R. O., Houlden, H., Salomons, G. S., Gleeson, J. G. <strong>Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly.</strong> Nature Commun. 11: 4038, 2020. Note: Electronic Article. Erratum: Nature Commun. 12: 1192, 2021. Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32788587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32788587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32788587[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/10.1038/s41467-020-17454-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32788587">Wang et al. (2020)</a> and <a href="#4" class="mim-tip-reference" title="Manole, A., Efthymiou, S., O'Connor, E., Mendes, M. I., Jennings, M., Maroofian, R., Davagnanam, I., Mankad, K., Lopez, M. R., Salpietro, V., Harripaul, R., Badalato, L., and 81 others. <strong>De novo and bi-allelic pathogenic variants in NARS1 cause neurodevelopmental delay due to toxic gain-of-function and partial loss-of-function effects.</strong> Am. J. Hum. Genet. 107: 311-324, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32738225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32738225</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32738225[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.06.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32738225">Manole et al. (2020)</a> identified a homozygous c.50C-T transition (c.50C-T, NM_004539.4) in the NARS1 gene, resulting in a thr17-to-met (T17M) substitution at a conserved residue in the UNE-N domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was present in heterozygous state in 4 individuals in the gnomAD database. Patient-derived cells showed decreased NARS1 protein expression, decreased homodimer formation, reduced aminoacylation activity, and impaired global protein synthesis compared to controls, consistent with a loss of function. Family history revealed 2 similarly affected sibs who died in childhood. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=32738225+32788587" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, IMPAIRED LANGUAGE, AND GAIT ABNORMALITIES</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">rs1908000933 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1908000933;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=rs1908000933" 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=rs1908000933" 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 sibs, born of unrelated Turkish parents (family MIC-2116, family 19), with neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG; <a href="/entry/619091">619091</a>), <a href="#6" class="mim-tip-reference" title="Wang, L., Li, Z., Sievert, D., Smith, D. E. C., Mendes, M. I., Chen, D. Y., Stanley, V., Ghosh, S., Wang, Y., Kara, M., Aslanger, A. D., Rosti, R. O., Houlden, H., Salomons, G. S., Gleeson, J. G. <strong>Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly.</strong> Nature Commun. 11: 4038, 2020. Note: Electronic Article. Erratum: Nature Commun. 12: 1192, 2021. Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32788587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32788587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32788587[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/10.1038/s41467-020-17454-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32788587">Wang et al. (2020)</a> and <a href="#4" class="mim-tip-reference" title="Manole, A., Efthymiou, S., O'Connor, E., Mendes, M. I., Jennings, M., Maroofian, R., Davagnanam, I., Mankad, K., Lopez, M. R., Salpietro, V., Harripaul, R., Badalato, L., and 81 others. <strong>De novo and bi-allelic pathogenic variants in NARS1 cause neurodevelopmental delay due to toxic gain-of-function and partial loss-of-function effects.</strong> Am. J. Hum. Genet. 107: 311-324, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32738225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32738225</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32738225[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.06.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32738225">Manole et al. (2020)</a> identified compound heterozygous mutations in the NARS1 gene: a 1-bp duplication (c.203dupA, NM_004539.4), resulting in a frameshift and premature termination (Met69AspfsTer4) in the N-terminal region, and a c.1067A-C transversion, resulting in an asp356-to-ala (D356A; <a href="#0003">108410.0003</a>) substitution at a conserved residue in the catalytic domain. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The frameshift was not found in the gnomAD database, whereas D356A was found in heterozygous state in 264 individuals. Cells derived from 1 patient showed decreased NARS1 protein expression, decreased homodimer formation, reduced aminoacylation activity, and impaired protein synthesis compared to controls, consistent with a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=32738225+32788587" 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>.0003 NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, IMPAIRED LANGUAGE, AND GAIT ABNORMALITIES</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs138016359 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs138016359;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/rs138016359?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=rs138016359" 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=rs138016359" 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=RCV001262914 OR RCV001267636 OR RCV001780213 OR RCV002252350 OR RCV004035403" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001262914, RCV001267636, RCV001780213, RCV002252350, RCV004035403" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001262914...</a>
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<p>For discussion of the c.1067A-C transversion (c.1067A-C, NM_004539.4) in the NARS1 gene, resulting in an asp356-to-ala (D356A) substitution, that was found in compound heterozygous state in 2 sibs with neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG; <a href="/entry/619091">619091</a>) by <a href="#6" class="mim-tip-reference" title="Wang, L., Li, Z., Sievert, D., Smith, D. E. C., Mendes, M. I., Chen, D. Y., Stanley, V., Ghosh, S., Wang, Y., Kara, M., Aslanger, A. D., Rosti, R. O., Houlden, H., Salomons, G. S., Gleeson, J. G. <strong>Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly.</strong> Nature Commun. 11: 4038, 2020. Note: Electronic Article. Erratum: Nature Commun. 12: 1192, 2021. Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32788587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32788587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32788587[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/10.1038/s41467-020-17454-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32788587">Wang et al. (2020)</a> and <a href="#4" class="mim-tip-reference" title="Manole, A., Efthymiou, S., O'Connor, E., Mendes, M. I., Jennings, M., Maroofian, R., Davagnanam, I., Mankad, K., Lopez, M. R., Salpietro, V., Harripaul, R., Badalato, L., and 81 others. <strong>De novo and bi-allelic pathogenic variants in NARS1 cause neurodevelopmental delay due to toxic gain-of-function and partial loss-of-function effects.</strong> Am. J. Hum. Genet. 107: 311-324, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32738225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32738225</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32738225[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.06.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32738225">Manole et al. (2020)</a>, see <a href="#0002">108410.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=32738225+32788587" 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 NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, IMPAIRED LANGUAGE, AND GAIT ABNORMALITIES</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs770931044 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs770931044;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/rs770931044?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=rs770931044" 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=rs770931044" 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=RCV001267637 OR RCV004570660" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001267637, RCV004570660" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001267637...</a>
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<p>In 15 patients from 7 unrelated families (families 9-15) with neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG; <a href="/entry/619091">619091</a>), <a href="#6" class="mim-tip-reference" title="Wang, L., Li, Z., Sievert, D., Smith, D. E. C., Mendes, M. I., Chen, D. Y., Stanley, V., Ghosh, S., Wang, Y., Kara, M., Aslanger, A. D., Rosti, R. O., Houlden, H., Salomons, G. S., Gleeson, J. G. <strong>Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly.</strong> Nature Commun. 11: 4038, 2020. Note: Electronic Article. Erratum: Nature Commun. 12: 1192, 2021. Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32788587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32788587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32788587[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/10.1038/s41467-020-17454-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32788587">Wang et al. (2020)</a> and <a href="#4" class="mim-tip-reference" title="Manole, A., Efthymiou, S., O'Connor, E., Mendes, M. I., Jennings, M., Maroofian, R., Davagnanam, I., Mankad, K., Lopez, M. R., Salpietro, V., Harripaul, R., Badalato, L., and 81 others. <strong>De novo and bi-allelic pathogenic variants in NARS1 cause neurodevelopmental delay due to toxic gain-of-function and partial loss-of-function effects.</strong> Am. J. Hum. Genet. 107: 311-324, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32738225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32738225</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32738225[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.06.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32738225">Manole et al. (2020)</a> identified a homozygous c.1633C-T transition (c.1633C-T, NM_004539.4) in the NARS1 gene, resulting in an arg545-to-cys (R545C) substitution at a conserved residue in the catalytic domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The variant was present in 5 heterozygotes in the gnomAD database. Western blot analysis of cells derived from 2 patients showed near normal protein levels, but functional studies demonstrated that the mutation resulted in reduced aminoacylation activity to about 40% of control values, consistent with a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=32738225+32788587" 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 NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, IMPAIRED LANGUAGE, AND GAIT ABNORMALITIES</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs771435243 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs771435243;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/rs771435243?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=rs771435243" 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=rs771435243" 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=RCV001267638" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001267638" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001267638</a>
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<p>In 2 sibs from Kosovo (family 16) with neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG; <a href="/entry/619091">619091</a>), <a href="#4" class="mim-tip-reference" title="Manole, A., Efthymiou, S., O'Connor, E., Mendes, M. I., Jennings, M., Maroofian, R., Davagnanam, I., Mankad, K., Lopez, M. R., Salpietro, V., Harripaul, R., Badalato, L., and 81 others. <strong>De novo and bi-allelic pathogenic variants in NARS1 cause neurodevelopmental delay due to toxic gain-of-function and partial loss-of-function effects.</strong> Am. J. Hum. Genet. 107: 311-324, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32738225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32738225</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32738225[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.06.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32738225">Manole et al. (2020)</a> identified a homozygous c.32G-C transversion (c.32G-C, NM_004539.4) in the NARS1 gene, resulting in an arg11-to-pro (R11P) substitution at the 5-prime end of the noncanonical UNE-N domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was found once in heterozygous state in the gnomAD database. Patient cells showed decreased NARS1 protein levels and a mild decrease in enzymatic activity (80% of controls). The authors suggested that this domain may have nontranslational functions that contribute to the phenotype. The patients had a severe form of the disorder with early-onset seizures and cerebral atrophy and delayed myelination on brain imaging. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32738225" 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 NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, IMPAIRED LANGUAGE, EPILEPSY, AND GAIT ABNORMALITIES</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">rs2051507892 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2051507892;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=rs2051507892" 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=rs2051507892" 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=RCV001262349 OR RCV001267639 OR RCV002274170 OR RCV002537635 OR RCV003127739" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001262349, RCV001267639, RCV002274170, RCV002537635, RCV003127739" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001262349...</a>
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<p>In 6 unrelated patients (patients 1-6) with neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG; <a href="/entry/619092">619092</a>), <a href="#4" class="mim-tip-reference" title="Manole, A., Efthymiou, S., O'Connor, E., Mendes, M. I., Jennings, M., Maroofian, R., Davagnanam, I., Mankad, K., Lopez, M. R., Salpietro, V., Harripaul, R., Badalato, L., and 81 others. <strong>De novo and bi-allelic pathogenic variants in NARS1 cause neurodevelopmental delay due to toxic gain-of-function and partial loss-of-function effects.</strong> Am. J. Hum. Genet. 107: 311-324, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32738225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32738225</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32738225[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.06.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32738225">Manole et al. (2020)</a> identified a de novo heterozygous c.1600C-T transition (c.1600C-T, NM_004539.4) in the NARS1 gene, resulting in an arg534-to-ter (R534X) substitution in the C terminus at a conserved residue 15 amino acids from the end of the protein. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Cells derived from 1 patient showed a dramatic decrease in enzyme activity compared to wildtype. Expression of this mutation in zebrafish caused cyclopia and gastrulation defects. The authors postulated a toxic gain-of-function dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32738225" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Beaulande1998" class="mim-anchor"></a>
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Beaulande, M., Tarbouriech, N., Hartlein, M.
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<strong>Human cytosolic asparaginyl-tRNA synthetase: cDNA sequence, functional expression in Escherichia coli and characterization as human autoantigen.</strong>
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Nucleic Acids Res. 26: 521-524, 1998.
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[<a href="https://doi.org/10.1093/nar/26.2.521" target="_blank">Full Text</a>]
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Cirullo, R. E., Arredondo-Vega, F. X., Smith, M., Wasmuth, J. J.
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<strong>Isolation and characterization of interspecific heat-resistant hybrids between a temperature-sensitive Chinese hamster cell asparaginyl-tRNA synthetase mutant and normal human leukocytes: assignment of human asnS gene to chromosome 18.</strong>
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Somat. Cell Genet. 9: 215-233, 1983.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6836455/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6836455</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6836455" 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/BF01543178" target="_blank">Full Text</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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Manole, A., Efthymiou, S., O'Connor, E., Mendes, M. I., Jennings, M., Maroofian, R., Davagnanam, I., Mankad, K., Lopez, M. R., Salpietro, V., Harripaul, R., Badalato, L., and 81 others.
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<strong>De novo and bi-allelic pathogenic variants in NARS1 cause neurodevelopmental delay due to toxic gain-of-function and partial loss-of-function effects.</strong>
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Am. J. Hum. Genet. 107: 311-324, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32738225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32738225</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32738225[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=32738225" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Shows, T. B.
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<strong>Personal Communication.</strong>
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Buffalo, N. Y. 1/11/1983.
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Wang, L., Li, Z., Sievert, D., Smith, D. E. C., Mendes, M. I., Chen, D. Y., Stanley, V., Ghosh, S., Wang, Y., Kara, M., Aslanger, A. D., Rosti, R. O., Houlden, H., Salomons, G. S., Gleeson, J. G.
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<strong>Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly.</strong>
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Nature Commun. 11: 4038, 2020. Note: Electronic Article. Erratum: Nature Commun. 12: 1192, 2021. Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32788587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32788587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32788587[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=32788587" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/s41467-020-17454-4" target="_blank">Full Text</a>]
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<a id="contributors" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="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>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 11/12/2020
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 08/29/2014<br>Carol A. Bocchini - updated : 10/27/2009
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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">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/4/1986
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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>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 02/25/2022
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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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alopez : 04/06/2021<br>carol : 11/18/2020<br>ckniffin : 11/12/2020<br>carol : 08/20/2019<br>alopez : 08/29/2014<br>carol : 10/27/2009<br>alopez : 7/29/1998<br>warfield : 4/7/1994<br>supermim : 3/16/1992<br>carol : 11/12/1990<br>supermim : 3/20/1990<br>ddp : 10/26/1989<br>marie : 3/25/1988
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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 class="container visible-print-block">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 108410
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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ASPARAGINYL-tRNA SYNTHETASE 1; NARS1
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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">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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NARS<br />
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ASNRS
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: NARS1</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 18q21.31
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Genomic coordinates <span class="small">(GRCh38)</span> : 18:57,600,656-57,621,836 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="2">
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<span class="mim-font">
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18q21.31
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</span>
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</td>
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<td>
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<span class="mim-font">
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Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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619091
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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619092
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<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>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The NARS1 gene encodes the cytoplasmic asparaginyl-tRNA synthetase that mediates the charging of the Asn amino acid onto its cognate transfer RNA, which is essential for protein synthesis (summary by Wang et al., 2020). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Cirullo et al. (1983) isolated hybrids between human peripheral leukocytes and a temperature-sensitive CHO cell line with a thermolabile asparaginyl-tRNA synthetase (EC 6.1.1.22), which they symbolized 'asnS.' Hybrids selected at 39 degrees C required the presence of human chromosome 18. Temperature-resistant hybrid cells contained 2 forms of ASNRS: 1 highly thermal resistant, like the human enzyme, and 1 highly thermolabile, like the CHO mutant enzyme. </p><p>Beaulande et al. (1998) cloned a human cytosolic ASNRS cDNA from a liver cDNA library. The deduced 548-amino acid protein has a predicted molecular mass of 62.9 kD and shares 53% sequence identity with the S. cerevisiae homolog. </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 1 catalytic-null splice variant for AsnRS. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using a DNA probe in human-rodent hybrid cells, Shows (1983) found that asparaginyl-tRNA synthetase segregated with peptidase A, a chromosome 18 marker.</p>
|
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By Western blot analysis, Beaulande et al. (1998) showed that a human autoimmune serum (anti-KS) neutralized human AsnRSc activity, suggesting that it is a class II aminoacyl-tRNA synthetase involved in autoimmune reactions. </p>
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</span>
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<div>
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<br />
|
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p><strong><em>Neurodevelopmental Disorder with Microcephaly, Impaired Language, and Gait Abnormalities</em></strong></p><p>
|
|
In 23 patients from 13 unrelated families with neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG; 619091), Wang et al. (2020) and Manole et al. (2020) identified homozygous or compound heterozygous mutations in the NARS1 gene (see, e.g., 108410.0001-108410.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Most of the mutations were missense, although 2 families carried a nonsense or frameshift mutation on 1 allele. Affected members of 7 consanguineous families (families 9-15) carried the same homozygous R545C mutation (108410.0004). Fibroblasts derived from 3 unrelated patients showed variably decreased NARS1 protein levels, impaired homodimerization, reduced cytoplasmic transferase activity, and decreased global protein synthesis compared to controls. These findings suggested that the mutations resulted in a loss of function. Induced neuronal progenitor cells derived from 2 unrelated patients were used to generate cultures of 3D cortical brain organoids (CO). Mutant organoids became progressively smaller with decreased diameter compared to controls beginning around division 52, modeling the microcephaly observed in the patients. Patient CO showed reduced generation of radial glial cells with abnormal neural rosette structure, depletion of rosettes and postmitotic neurons, and decreased proliferation and viability of progenitor cells compared to wildtype. RNA-seq analysis of patient cells detected abnormalities in cell cycle control and neuronal progenitor cell fate differentiation, suggesting a role for NARS1 in these processes. </p><p><strong><em>Neurodevelopmental Disorder with Microcephaly, Impaired Language, Epilepsy, and Gait Abnormalities</em></strong></p><p>
|
|
In 6 unrelated patients (patients 1-6) with neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG; 619092), Manole et al. (2020) identified a de novo heterozygous nonsense mutation in the NARS1 gene (R534X; 108410.0006). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Cells derived from 1 patient showed a dramatic decrease in enzyme activity compared to wildtype. Expression of this mutation in zebrafish caused cyclopia and gastrulation defects. The authors postulated a toxic gain-of-function dominant-negative effect. Two additional patients (patients 7 and 8) with a similar disorder but without microcephaly carried de novo heterozygous missense variants in the NARS1 gene (G509S and R322L) that were not present in the gnomAD database. Functional studies of these variants were not performed. </p>
|
|
</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">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>6 Selected Examples):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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|
<div>
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, IMPAIRED LANGUAGE, AND GAIT ABNORMALITIES</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
NARS1, THR17MET
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<br />
|
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|
|
SNP: rs148893823,
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|
|
gnomAD: rs148893823,
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|
|
ClinVar: RCV001267640
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 8-year-old girl, born of consanguineous parents from Libya (family MIC-1433, family 17), with neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG; 619091), Wang et al. (2020) and Manole et al. (2020) identified a homozygous c.50C-T transition (c.50C-T, NM_004539.4) in the NARS1 gene, resulting in a thr17-to-met (T17M) substitution at a conserved residue in the UNE-N domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was present in heterozygous state in 4 individuals in the gnomAD database. Patient-derived cells showed decreased NARS1 protein expression, decreased homodimer formation, reduced aminoacylation activity, and impaired global protein synthesis compared to controls, consistent with a loss of function. Family history revealed 2 similarly affected sibs who died in childhood. </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>.0002 NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, IMPAIRED LANGUAGE, AND GAIT ABNORMALITIES</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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NARS1, 1-BP DUP, 203A
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<br />
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SNP: rs1908000933,
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ClinVar: RCV001267635
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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 sibs, born of unrelated Turkish parents (family MIC-2116, family 19), with neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG; 619091), Wang et al. (2020) and Manole et al. (2020) identified compound heterozygous mutations in the NARS1 gene: a 1-bp duplication (c.203dupA, NM_004539.4), resulting in a frameshift and premature termination (Met69AspfsTer4) in the N-terminal region, and a c.1067A-C transversion, resulting in an asp356-to-ala (D356A; 108410.0003) substitution at a conserved residue in the catalytic domain. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The frameshift was not found in the gnomAD database, whereas D356A was found in heterozygous state in 264 individuals. Cells derived from 1 patient showed decreased NARS1 protein expression, decreased homodimer formation, reduced aminoacylation activity, and impaired protein synthesis compared to controls, consistent with a loss of function. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0003 NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, IMPAIRED LANGUAGE, AND GAIT ABNORMALITIES</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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NARS1, ASP356ALA
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<br />
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SNP: rs138016359,
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gnomAD: rs138016359,
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ClinVar: RCV001262914, RCV001267636, RCV001780213, RCV002252350, RCV004035403
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the c.1067A-C transversion (c.1067A-C, NM_004539.4) in the NARS1 gene, resulting in an asp356-to-ala (D356A) substitution, that was found in compound heterozygous state in 2 sibs with neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG; 619091) by Wang et al. (2020) and Manole et al. (2020), see 108410.0002. </p>
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<h4>
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<span class="mim-font">
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<strong>.0004 NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, IMPAIRED LANGUAGE, AND GAIT ABNORMALITIES</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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NARS1, ARG545CYS
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<br />
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SNP: rs770931044,
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gnomAD: rs770931044,
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ClinVar: RCV001267637, RCV004570660
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<p>In 15 patients from 7 unrelated families (families 9-15) with neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG; 619091), Wang et al. (2020) and Manole et al. (2020) identified a homozygous c.1633C-T transition (c.1633C-T, NM_004539.4) in the NARS1 gene, resulting in an arg545-to-cys (R545C) substitution at a conserved residue in the catalytic domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The variant was present in 5 heterozygotes in the gnomAD database. Western blot analysis of cells derived from 2 patients showed near normal protein levels, but functional studies demonstrated that the mutation resulted in reduced aminoacylation activity to about 40% of control values, consistent with a loss of function. </p>
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</span>
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</div>
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<h4>
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<span class="mim-font">
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<strong>.0005 NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, IMPAIRED LANGUAGE, AND GAIT ABNORMALITIES</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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NARS1, ARG11PRO
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<br />
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SNP: rs771435243,
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gnomAD: rs771435243,
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ClinVar: RCV001267638
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<span class="mim-text-font">
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<p>In 2 sibs from Kosovo (family 16) with neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities (NEDMILG; 619091), Manole et al. (2020) identified a homozygous c.32G-C transversion (c.32G-C, NM_004539.4) in the NARS1 gene, resulting in an arg11-to-pro (R11P) substitution at the 5-prime end of the noncanonical UNE-N domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was found once in heterozygous state in the gnomAD database. Patient cells showed decreased NARS1 protein levels and a mild decrease in enzymatic activity (80% of controls). The authors suggested that this domain may have nontranslational functions that contribute to the phenotype. The patients had a severe form of the disorder with early-onset seizures and cerebral atrophy and delayed myelination on brain imaging. </p>
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</span>
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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>.0006 NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, IMPAIRED LANGUAGE, EPILEPSY, AND GAIT ABNORMALITIES</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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NARS1, ARG534TER
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<br />
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SNP: rs2051507892,
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ClinVar: RCV001262349, RCV001267639, RCV002274170, RCV002537635, RCV003127739
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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 6 unrelated patients (patients 1-6) with neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG; 619092), Manole et al. (2020) identified a de novo heterozygous c.1600C-T transition (c.1600C-T, NM_004539.4) in the NARS1 gene, resulting in an arg534-to-ter (R534X) substitution in the C terminus at a conserved residue 15 amino acids from the end of the protein. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Cells derived from 1 patient showed a dramatic decrease in enzyme activity compared to wildtype. Expression of this mutation in zebrafish caused cyclopia and gastrulation defects. The authors postulated a toxic gain-of-function dominant-negative effect. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Beaulande, M., Tarbouriech, N., Hartlein, M.
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<strong>Human cytosolic asparaginyl-tRNA synthetase: cDNA sequence, functional expression in Escherichia coli and characterization as human autoantigen.</strong>
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Nucleic Acids Res. 26: 521-524, 1998.
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[PubMed: 9421509]
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[Full Text: https://doi.org/10.1093/nar/26.2.521]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Cirullo, R. E., Arredondo-Vega, F. X., Smith, M., Wasmuth, J. J.
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<strong>Isolation and characterization of interspecific heat-resistant hybrids between a temperature-sensitive Chinese hamster cell asparaginyl-tRNA synthetase mutant and normal human leukocytes: assignment of human asnS gene to chromosome 18.</strong>
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Somat. Cell Genet. 9: 215-233, 1983.
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[PubMed: 6836455]
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[Full Text: https://doi.org/10.1007/BF01543178]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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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: 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">
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Manole, A., Efthymiou, S., O'Connor, E., Mendes, M. I., Jennings, M., Maroofian, R., Davagnanam, I., Mankad, K., Lopez, M. R., Salpietro, V., Harripaul, R., Badalato, L., and 81 others.
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|
<strong>De novo and bi-allelic pathogenic variants in NARS1 cause neurodevelopmental delay due to toxic gain-of-function and partial loss-of-function effects.</strong>
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Am. J. Hum. Genet. 107: 311-324, 2020.
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[PubMed: 32738225]
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[Full Text: https://doi.org/10.1016/j.ajhg.2020.06.016]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Shows, T. B.
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<strong>Personal Communication.</strong>
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Buffalo, N. Y. 1/11/1983.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Wang, L., Li, Z., Sievert, D., Smith, D. E. C., Mendes, M. I., Chen, D. Y., Stanley, V., Ghosh, S., Wang, Y., Kara, M., Aslanger, A. D., Rosti, R. O., Houlden, H., Salomons, G. S., Gleeson, J. G.
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|
<strong>Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly.</strong>
|
|
Nature Commun. 11: 4038, 2020. Note: Electronic Article. Erratum: Nature Commun. 12: 1192, 2021. Electronic Article.
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[PubMed: 32788587]
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[Full Text: https://doi.org/10.1038/s41467-020-17454-4]
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</p>
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</li>
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</ol>
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<div>
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<br />
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Contributors:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 11/12/2020<br>Ada Hamosh - updated : 08/29/2014<br>Carol A. Bocchini - updated : 10/27/2009
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/4/1986
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</span>
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alopez : 02/25/2022<br>alopez : 04/06/2021<br>carol : 11/18/2020<br>ckniffin : 11/12/2020<br>carol : 08/20/2019<br>alopez : 08/29/2014<br>carol : 10/27/2009<br>alopez : 7/29/1998<br>warfield : 4/7/1994<br>supermim : 3/16/1992<br>carol : 11/12/1990<br>supermim : 3/20/1990<br>ddp : 10/26/1989<br>marie : 3/25/1988
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