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Entry
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- *600287 - GLYCYL-tRNA SYNTHETASE 1; GARS1
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- OMIM
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<p>
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<span class="h4">*600287</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/600287">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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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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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 class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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<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=ENSG00000106105;t=ENST00000389266" 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=2617" 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=600287" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="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=ENSG00000106105;t=ENST00000389266" 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_001316772,NM_002047" 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_002047" 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=600287" 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=02617&isoform_id=02617_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/GARS1" 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/493066,600727,1311463,3845409,14043463,14043544,41350064,51105865,116805340,119614366,119614367,193786641,194380518,313104283,943350815" 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/P41250" 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=2617" 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=ENSG00000106105;t=ENST00000389266" 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=GARS1" 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=GARS1" 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+2617" 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/GARS1" 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:2617" 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/2617" 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=chr7&hgg_gene=ENST00000389266.8&hgg_start=30594735&hgg_end=30634033&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 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:4162" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/gars1" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=600287[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=600287[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000106105" 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=GARS1" 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=GARS1" 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=GARS1" 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="http://www.molgen.ua.ac.be/CMTMutations/" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=GARS1&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/PA28575" 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:4162" 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/FBgn0027088.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:2449057" 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/GARS1#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:2449057" 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/2617/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=2617" 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=WBGene00001744;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-030131-9174" 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="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" 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="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</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="mimCellLinesLinksFold" 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://catalog.coriell.org/Search?q=OmimNum:600287" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</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:2617" 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=GARS1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 1197152005, 717011006<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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600287
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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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GLYCYL-tRNA SYNTHETASE 1; GARS1
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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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GARS
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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=GARS1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">GARS1</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/7/165?start=-3&limit=10&highlight=165">7p14.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr7:30594735-30634033&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'})">7:30,594,735-30,634,033</a> </span>
|
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</em>
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=601472,600794,619042" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
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</span>
|
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|
</th>
|
|
<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>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/7/165?start=-3&limit=10&highlight=165">
|
|
7p14.3
|
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</a>
|
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</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
Charcot-Marie-Tooth disease, type 2D
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
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|
<a href="/entry/601472"> 601472 </a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal 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">
|
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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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<p>The GARS1 gene encodes glycyl-tRNA synthetase, an enzyme that is responsible for covalently attaching glycine to its cognate tRNA, which is essential for protein translation. Unlike most other tRNA synthetase genes, GARS1 encodes both the cytoplasmic and mitochondrial isoforms of the enzyme. The mitochondrial isoform contains a mitochondrial targeting signal (MTS) (summary by <a href="#3" class="mim-tip-reference" title="Boczonadi, V., Meyer, K., Gonczarowska-Jorge, H., Griffin, H., Roos, A., Bartsakoulia, M., Bansagi, B., Ricci, G., Palinkas, F., Zahedi, R. P., Bruni, F., Kaspar, B., Lochmuller, H., Boycott, K. M., Muller, J. S., Horvath, R. <strong>Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons.</strong> Hum. Molec. Genet. 27: 2187-2204, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29648643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29648643</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29648643[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/10.1093/hmg/ddy127" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29648643">Boczonadi et al., 2018</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29648643" 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>Aminoacyl-tRNA synthetases perform an essential function in protein synthesis by catalyzing the esterification of an amino acid to its cognate tRNA. These enzymes are necessarily present in each cell and must properly recognize the tRNA and the amino acid in order to maintain fidelity of translation. From the primary structures, 2 distinct classes of synthetases have been recognized, with similarity of certain structural features, amino acid attachment sites, and other properties between members of a class. Certain aminoacyl-tRNA synthetases are autoantigens in patients with the idiopathic inflammatory myopathies, polymyositis, and dermatomyositis. Autoantibodies reactive with synthetases are found almost exclusively in these conditions, with individuals usually having autoantibodies to only a single synthetase. Most commonly they are directed at histidyl-tRNA synthetase (<a href="/entry/142810">142810</a>), labeled 'anti-Jo-1' autoantibodies. <a href="#9" class="mim-tip-reference" title="Ge, Q., Trieu, E. P., Targoff, I. N. <strong>Primary structure and functional expression of human glycyl-tRNA synthetase, an autoantigen in myositis.</strong> J. Biol. Chem. 269: 28790-28797, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7961834/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7961834</a>]" pmid="7961834">Ge et al. (1994)</a> used a cDNA encoding the human form of glycyl-tRNA synthetase for isolation of corresponding cDNAs. <a href="#22" class="mim-tip-reference" title="Shiba, K., Schimmel, P., Motegi, H., Noda, T. <strong>Human glycyl-tRNA synthetase: wide divergence of primary structure from bacterial counterpart and species-specific aminoacylation.</strong> J. Biol. Chem. 269: 30049-30055, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7962006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7962006</a>]" pmid="7962006">Shiba et al. (1994)</a> likewise cloned a class II human glycyl-tRNA synthetase and compared its structure with that of the bacterial counterpart from which it was found to diverge widely. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7961834+7962006" 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="#25" class="mim-tip-reference" title="Williams, J., Osvath, S., Khong, T. F., Pearse, M., Power, D. <strong>Cloning, sequencing and bacterial expression of human glycine tRNA synthetase.</strong> Nucleic Acids Res. 23: 1307-1310, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7753621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7753621</a>] [<a href="https://doi.org/10.1093/nar/23.8.1307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7753621">Williams et al. (1995)</a> also cloned the human GARS cDNA. The predicted 685-amino acid protein showed approximately 45% identity to the yeast protein. The recombinantly expressed protein was immunoprecipitated with human serum containing autoantibodies to glycyl-tRNA synthetase and was shown to catalyze the aminoacylation of tRNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7753621" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#3" class="mim-tip-reference" title="Boczonadi, V., Meyer, K., Gonczarowska-Jorge, H., Griffin, H., Roos, A., Bartsakoulia, M., Bansagi, B., Ricci, G., Palinkas, F., Zahedi, R. P., Bruni, F., Kaspar, B., Lochmuller, H., Boycott, K. M., Muller, J. S., Horvath, R. <strong>Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons.</strong> Hum. Molec. Genet. 27: 2187-2204, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29648643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29648643</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29648643[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/10.1093/hmg/ddy127" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29648643">Boczonadi et al. (2018)</a> demonstrated that GARS1 localizes to mitochondrial RNA granules in human fibroblasts and oligodendroglial cells, indicating that it likely plays a role in mitochondrial translation. siRNA-mediated knockdown of the GARS1 gene resulted in reduced mitochondrial translation and decreased protein levels of respiratory chain subunits in oligodendroglial cells and myoblasts, but not in fibroblasts, suggesting tissue-specific functions. Detailed functional studies also suggested that GARS1 may have a noncanonical role in calcium metabolism, endoplasmic reticulum (ER) interactions, vesicle dynamics, and autophagy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29648643" 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="#17" class="mim-tip-reference" title="Nichols, R. C., Pai, S. I., Ge, Q., Targoff, I. N., Plotz, P. H., Liu, P. <strong>Localization of two human autoantigen genes by PCR screening and in situ hybridization--Glycyl-tRNA synthetase locates to 7p15 and alanyl-tRNA synthetase locates to 16q22.</strong> Genomics 30: 131-132, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8595897/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8595897</a>] [<a href="https://doi.org/10.1006/geno.1995.0028" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8595897">Nichols et al. (1995)</a> mapped the GARS gene to chromosome 7p15 by FISH analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8595897" 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="#24" class="mim-tip-reference" title="Stumpf, A. M. <strong>Personal Communication.</strong> Baltimore, Md. 10/15/2020."None>Stumpf (2020)</a> mapped the GARS1 gene to chromosome 17p14.3 based on an alignment of the GARS1 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=BC007755" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">BC007755</a>) with the genomic sequence (GRCh38).</p>
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<p><strong><em>Charcot-Marie-Tooth Disease Type 2D</em></strong></p><p>
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<a href="#2" class="mim-tip-reference" title="Antonellis, A., Ellsworth, R. E., Sambuughin, N., Puls, I., Abel, A., Lee-Lin, S.-Q., Jordanova, A., Kremensky, I., Christodoulou, K., Middleton, L. T., Sivakumar, K., Ionasescu, V., Funalot, B., Vance, J. M., Goldfarb, L. G., Fischbeck, K. H., Green, E. D. <strong>Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V.</strong> Am. J. Hum. Genet. 72: 1293-1299, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12690580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12690580</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12690580[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/10.1086/375039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12690580">Antonellis et al. (2003)</a> identified heterozygous mutations in the GARS1 gene (e.g., <a href="#0001">600287.0001</a>) in families with Charcot-Marie-Tooth disease type 2D (CMT2D; <a href="/entry/601472">601472</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12690580" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 Malian sibs with CMT2D, <a href="#26" class="mim-tip-reference" title="Yalcouye, A., Diallo, S. H., Coulibaly, T., Cisse, L., Diallo, S., Samassekou, O., Diarra, S., Coulibaly, D., Keita, M., Guinto, C. O., Fischbeck, K., Landoure, G., The H3Africa Consortium. <strong>A novel mutation in the GARS gene in a Malian family with Charcot-Marie-Tooth disease.</strong> Molec. Genet. Genomic Med. 7: e782, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31173493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31173493</a>] [<a href="https://doi.org/10.1002/mgg3.782" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31173493">Yalcouye et al. (2019)</a> identified a heterozygous mutation in the GARS1 gene (S265Y; <a href="#0012">600287.0012</a>) by next-generation sequencing of a panel of 50 genes associated with CMT. The patients' mother also had the mutation but was asymptomatic, suggesting variable penetrance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31173493" 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>Distal Hereditary Motor Neuronopathy 5, Autosomal Dominant</em></strong></p><p>
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<a href="#2" class="mim-tip-reference" title="Antonellis, A., Ellsworth, R. E., Sambuughin, N., Puls, I., Abel, A., Lee-Lin, S.-Q., Jordanova, A., Kremensky, I., Christodoulou, K., Middleton, L. T., Sivakumar, K., Ionasescu, V., Funalot, B., Vance, J. M., Goldfarb, L. G., Fischbeck, K. H., Green, E. D. <strong>Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V.</strong> Am. J. Hum. Genet. 72: 1293-1299, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12690580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12690580</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12690580[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/10.1086/375039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12690580">Antonellis et al. (2003)</a> identified heterozygous mutations in the GARS1 gene (e.g., <a href="#0002">600287.0002</a>) in families with autosomal dominant distal hereditary motor neuronopathy-5 (HMND5; <a href="/entry/600794">600794</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12690580" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient (patient 1) and his mother with HMND5, <a href="#3" class="mim-tip-reference" title="Boczonadi, V., Meyer, K., Gonczarowska-Jorge, H., Griffin, H., Roos, A., Bartsakoulia, M., Bansagi, B., Ricci, G., Palinkas, F., Zahedi, R. P., Bruni, F., Kaspar, B., Lochmuller, H., Boycott, K. M., Muller, J. S., Horvath, R. <strong>Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons.</strong> Hum. Molec. Genet. 27: 2187-2204, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29648643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29648643</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29648643[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/10.1093/hmg/ddy127" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29648643">Boczonadi et al. (2018)</a> identified a heterozygous missense mutation in the GARS1 gene (H216R; <a href="#0008">600287.0008</a>). The mutation was identified through sequencing of a gene panel. Patient fibroblasts did not show a defect in mitochondrial translation, but detailed studies on induced neuronal progenitor cells derived from patient fibroblasts showed decreased levels of mitochondrial respiratory chain complexes, impaired mitochondrial respiration and metabolism, defects in calcium flux dynamics, and increased autophagic vacuoles. These findings were consistent with tissue-specific effects of the mutation; the authors postulated a dominant gain-of-function mechanism. The patients had onset of upper limb-predominant distal neuropathy in their early twenties. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29648643" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 7 unrelated patients with HMND5, <a href="#8" class="mim-tip-reference" title="Forrester, N., Rattihalli, R., Horvath, R., Maggi, L., Manzur, A., Fuller, G., Gutowski, N., Rankin, J., Dick, D., Buxton, C., Greenslade, M., Majumdar, A. <strong>Clinical and genetic features in a series of eight unrelated patients with neuropathy due to glycyl-tRNA synthetase (GARS) variants.</strong> J. Neuromusc. Dis. 7: 137-143, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31985473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31985473</a>] [<a href="https://doi.org/10.3233/JND-200472" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31985473">Forrester et al. (2020)</a> identified heterozygous missense variants in the GARS1 gene (see, e.g., H472R, <a href="#0013">600287.0013</a>). The variants, which were found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in affected family members of 6 probands, whereas it occurred de novo in 1 patient. Although functional studies of the variants were not performed, 3 (H216R, G327R, and H472R) were classified as pathogenic or likely pathogenic, and 3 were considered to be of uncertain pathogenic significance (R27P, K510Q, and M555V), according to ACMG criteria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31985473" 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>Infantile Spinal Muscular Atrophy, James Type</em></strong></p><p>
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In a 7-year-old girl, born of unrelated parents (family 1), with the James type of infantile spinal muscular atrophy (SMAJI; <a href="/entry/619042">619042</a>), <a href="#13" class="mim-tip-reference" title="James, P. A., Cader, M. Z., Muntoni, F., Childs, A.-M., Crow, Y. J., Talbot, K. <strong>Severe childhood SMA and axonal CMT due to anticodon binding domain mutations in the GARS gene.</strong> Neurology 67: 1710-1712, 2006. Note: Erratum: Neurology 68: 711 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17101916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17101916</a>] [<a href="https://doi.org/10.1212/01.wnl.0000242619.52335.bc" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17101916">James et al. (2006)</a> identified a de novo heterozygous missense mutation in the GARS1 gene (G598A; <a href="#0007">600287.0007</a>). Functional studies of the variant were not performed. The patient presented at 6 months of age with lower extremity weakness and did not achieve independent ambulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17101916" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 14-month-old infant (patient 2) with SMAJI, <a href="#8" class="mim-tip-reference" title="Forrester, N., Rattihalli, R., Horvath, R., Maggi, L., Manzur, A., Fuller, G., Gutowski, N., Rankin, J., Dick, D., Buxton, C., Greenslade, M., Majumdar, A. <strong>Clinical and genetic features in a series of eight unrelated patients with neuropathy due to glycyl-tRNA synthetase (GARS) variants.</strong> J. Neuromusc. Dis. 7: 137-143, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31985473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31985473</a>] [<a href="https://doi.org/10.3233/JND-200472" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31985473">Forrester et al. (2020)</a> identified a heterozygous missense mutation in the GARS1 gene (E125K; <a href="#0009">600287.0009</a>). The mutation was found by next-generation sequencing and confirmed by Sanger sequencing; functional studies and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31985473" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 unrelated children with SMAJI, <a href="#15" class="mim-tip-reference" title="Markovitz, R., Ghosh, R., Kuo, M. E., Hong, W., Lim, J., Bernes, S., Manberg, S., Crosby, K., Tanpaiboon, P., Bharucha-Goebel, D., Bonnemann, C., Mohila, C. A., Mizerik, E., Woodbury, S., Bi, W., Lotze, T., Antonellis, A., Xiao, R., Potocki, L. GARS-related disease in infantile spinal muscular atrophy. <strong>implications for diagnosis and treatment.</strong> Am. J. Med. Genet. 182A: 1167-1176, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32181591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32181591</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32181591[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.61544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32181591">Markovitz et al. (2020)</a> identified de novo heterozygous missense mutations in the GARS1 gene (I334N, <a href="#0010">600287.0010</a> and G652R, <a href="#0011">600287.0011</a>). The mutations, which were found by trio-based exome sequencing, were not present in the gnomAD database. In vitro functional complementation studies showed that the I334N variant was unable to rescue the growth defect phenotype in yeast, consistent with a loss-of-function effect. Functional studies of the G652R variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32181591" 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>Variant Function</em></strong></p><p>
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<a href="#10" class="mim-tip-reference" title="Griffin, L. B., Sakaguchi, R., McGuigan, D., Gonzalez, M. A., Searby, C., Zuchner, S., Hou, Y.-M., Antonellis, A. <strong>Impaired function is a common feature of neuronopathy-associated glycyl-tRNA synthetase mutations.</strong> Hum. Mutat. 35: 1363-1371, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25168514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25168514</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25168514[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.22681" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25168514">Griffin et al. (2014)</a> demonstrated that several missense mutations in the GARS gene previously associated with CMT2D and/or HMND5 had less than 10% aminoacylation activity compared to wildtype. These pathogenic mutations included G240R (<a href="#0001">600287.0001</a>), G526R (<a href="#0004">600287.0004</a>), D146N, S211F, P244L (<a href="#0006">600287.0006</a>), I280F, H418R, and G598A (<a href="#0007">600287.0007</a>). A57V retained about 50% residual activity. Site-directed mutagenesis studies in yeast showed that the D146N and P244L mutations resulted in a severe reduction in cell growth compared to wildtype. Finally, the S211F, P244L, I280F, and G598A mutant proteins did not associate normally with puncta in a neuroblastoma cell line, suggesting that reduced localization to axons may be a component of CMT2D and HMND5 pathogenesis. The findings were consistent with some of the mutations causing a loss of GARS function. However, the E71G (<a href="#0003">600287.0003</a>) and D500N (<a href="#0005">600287.0005</a>) mutations did not show impaired function in any of the assays used in the study. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25168514" 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="#11" class="mim-tip-reference" title="He, W., Bai, G., Zhou, H., Wei, N., White, N. M., Lauer, J., Liu, H., Shi, Y., Dumitru, C. D., Lettieri, K., Shubayev, V., Jordanova, A., Guergueltcheva, V., Griffin, P. R., Burgess, R. W., Pfaff, S. L., Yang, X.-L. <strong>CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase.</strong> Nature 526: 710-714, 2015. Note: Erratum: Nature 532: 402 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26503042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26503042</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26503042[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/nature15510" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26503042">He et al. (2015)</a> determined that several mutations in the GARS gene that cause CMT2D, including G240R (<a href="#0001">600287.0001</a>), L129P (<a href="#0002">600287.0002</a>), and E71G (<a href="#0003">600287.0003</a>), as well as a pro234-to-lys-tyr (P234KY) substitution in mouse, open a new protein-interaction surface on mutant GARS protein. Using in vitro protein pull-down and coimmunoprecipitation assays, the authors found that GARS(P234KY), GARS(L129P), GARS(G240R), and GARS(E71G) but not wildtype GARS, bound to NRP1 (<a href="/entry/602069">602069</a>), a VEGFA (<a href="/entry/192240">192240</a>) receptor required for motor neuron axon guidance and cell body migration. NRP1 coprecipitated GARS(P234KY) from mutant mice and GARS(L129P) in human lymphocytes much more readily than wildtype GARS. GARS(P234KY), but not wildtype GARS, competed with VEGFA for binding the extracellular b1 domain of NRP1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26503042" 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>Associations Pending Confirmation</em></strong></p><p>
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<a href="#16" class="mim-tip-reference" title="McMillan, H. J., Schwartzentruber, J., Smith, A., Lee, S., Chakraborty, P., Bulman, D. E., Beaulieu, C. L., Majewski, J., Boycott, K. M., Geraghty, M. T. <strong>Compound heterozygous mutations in glycyl-tRNA synthetase are a proposed cause of systemic mitochondrial disease.</strong> BMC Med. Genet. 15: 36, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24669931/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24669931</a>] [<a href="https://doi.org/10.1186/1471-2350-15-36" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24669931">McMillan et al. (2014)</a> reported a 12-year-old girl, born of unrelated parents, with evidence of a systemic mitochondrial disorder. Exome sequencing identified compound heterozygous missense variants in the GARS1 gene (S635L and R596Q). Both variants occurred at highly conserved residues in the anticodon binding domain. The variants segregated with the disorder in the family: the unaffected mother carried the R596Q variant, whereas the father, who had a mild sensorimotor polyneuropathy, carried S635L. In addition, the proband carried a heterozygous variant in the MIB1 gene (<a href="/entry/608677">608677</a>), which is associated with left ventricular noncompaction-7 (LVNC7; <a href="/entry/615092">615092</a>), which may have contributed to her cardiomyopathy. However, the MIB1 variant was also present in her father, who did not have cardiac disease. The patient had evidence of a systemic mitochondrial disorder, with exercise-induced myalgia, increased serum lactate and alanine, white matter abnormalities on brain imaging, and cardiomyopathy. Functional studies of the variants and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24669931" 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="Boczonadi, V., Meyer, K., Gonczarowska-Jorge, H., Griffin, H., Roos, A., Bartsakoulia, M., Bansagi, B., Ricci, G., Palinkas, F., Zahedi, R. P., Bruni, F., Kaspar, B., Lochmuller, H., Boycott, K. M., Muller, J. S., Horvath, R. <strong>Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons.</strong> Hum. Molec. Genet. 27: 2187-2204, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29648643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29648643</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29648643[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/10.1093/hmg/ddy127" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29648643">Boczonadi et al. (2018)</a> performed functional studies of cells derived from the girl (patient 2) and her father (carrier 2) reported by <a href="#16" class="mim-tip-reference" title="McMillan, H. J., Schwartzentruber, J., Smith, A., Lee, S., Chakraborty, P., Bulman, D. E., Beaulieu, C. L., Majewski, J., Boycott, K. M., Geraghty, M. T. <strong>Compound heterozygous mutations in glycyl-tRNA synthetase are a proposed cause of systemic mitochondrial disease.</strong> BMC Med. Genet. 15: 36, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24669931/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24669931</a>] [<a href="https://doi.org/10.1186/1471-2350-15-36" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24669931">McMillan et al. (2014)</a>. Although patient fibroblasts did not show a mitochondrial translation defect, induced neural progenitor cells derived from patient fibroblasts showed decreased levels of respiratory complex I subunit NDUFB8 (<a href="/entry/602140">602140</a>), as well as subtle defects in mitochondrial metabolism and fatty acid-beta oxidation. The authors postulated that recessive GARS1 variants may result in a loss-of-function effect with tissue-specific manifestations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=24669931+29648643" 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="#18" class="mim-tip-reference" title="Oprescu, S. N., Chepa-Lotrea, X., Takase, R., Golas, G., Markello, T. C., Adams, D. R., Toro, C., Gropman, A. L., Hou, Y.-M., Malicdan, M. C. V., Gahl, W. A., Tifft, C. J., Antonellis, A. <strong>Compound heterozygosity for loss-of-function GARS variants results in a multisystem developmental syndrome that includes severe growth retardation.</strong> Hum. Mutat. 38: 1412-1420, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28675565/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28675565</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28675565[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.23287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28675565">Oprescu et al. (2017)</a> reported a 7-year-old girl (UDP5316), born of unrelated Caucasian parents, with a severe multisystem developmental disorder. Exome sequencing identified 2 variants in the GARS1 gene: a 4-bp deletion (c.246_249del), resulting in a frameshift and premature termination (Glu83IlefsTer6), and R310Q, which affected a conserved residue in the catalytic domain. Each unaffected parent carried 1 of the variants; neither variant was present in the gnomAD database. In vitro functional studies showed that both variants resulted in a loss-of-function effect on GARS1 activity. The patient was born at 36 weeks' gestation by cesarean section due to intrauterine growth retardation. She showed failure to thrive and global developmental delay, with independent walking at 6 years, pincer grasp at 5 years, and language delay with poor intelligibility. At age 3 years, she was microcephalic with abnormal skull shape and patent anterior fontanel. Dysmorphic features included sparse thin hair, triangular face with broad forehead, epicanthal folds, hypotelorism, smooth philtrum, and high-arched palate. She had upper motor neuron signs with hyperreflexia and spasticity of the lower limbs, but no evidence of lower motor neuron dysfunction or neuropathy. Sensation was normal. Additional features included retinal changes with depigmentation, sensorineural hearing loss, atrial septal defect, pulmonic stenosis, sleep apnea, atopic dermatitis, recurrent rhinitis, and fused cervical vertebrae. Brain imaging showed thin corpus callosum, mild atrophy of the cerebellar vermis, small brainstem, delayed myelination, and enlarged ventricles. Skeletal muscle biopsy was not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28675565" 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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Using positional cloning, <a href="#21" class="mim-tip-reference" title="Seburn, K. L., Nangle, L. A., Cox, G. A., Schimmel, P., Burgess, R. W. <strong>An active dominant mutation of glycyl-tRNA synthetase causes neuropathy in a Charcot-Marie-Tooth 2D mouse model.</strong> Neuron 51: 715-726, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16982418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16982418</a>] [<a href="https://doi.org/10.1016/j.neuron.2006.08.027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16982418">Seburn et al. (2006)</a> found that a mutagenesis-induced dominant mouse model Nmf249 was caused by an in-frame indel mutation at pro278 in the Gars gene. Affected mice had a sensorimotor polyneuropathy with overt neuromuscular dysfunction by 3 weeks of age, smaller size, and shortened life spans compared to wildtype mice. Mutant mice showed neurodegenerative changes at the neuromuscular junction, with more severe changes at distal muscles. Nerve conduction velocities were severely decreased, and peripheral nerves showed reduced axonal diameters and loss of large-diameter axons, but no evidence of demyelination. Homozygous mutant mice were embryonic lethal. The affected pro278 residue is near the catalytic domain-2 of the protein, but the mutation did not affect Gars mRNA levels, and the recombinant mutant enzyme showed normal kinetics and activity. The findings were not consistent with either loss of function (haploinsufficiency) or a dominant-negative loss-of-function effect, but <a href="#21" class="mim-tip-reference" title="Seburn, K. L., Nangle, L. A., Cox, G. A., Schimmel, P., Burgess, R. W. <strong>An active dominant mutation of glycyl-tRNA synthetase causes neuropathy in a Charcot-Marie-Tooth 2D mouse model.</strong> Neuron 51: 715-726, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16982418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16982418</a>] [<a href="https://doi.org/10.1016/j.neuron.2006.08.027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16982418">Seburn et al. (2006)</a> postulated aberrant pathogenic function of the mutant protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16982418" 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="#11" class="mim-tip-reference" title="He, W., Bai, G., Zhou, H., Wei, N., White, N. M., Lauer, J., Liu, H., Shi, Y., Dumitru, C. D., Lettieri, K., Shubayev, V., Jordanova, A., Guergueltcheva, V., Griffin, P. R., Burgess, R. W., Pfaff, S. L., Yang, X.-L. <strong>CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase.</strong> Nature 526: 710-714, 2015. Note: Erratum: Nature 532: 402 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26503042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26503042</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26503042[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/nature15510" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26503042">He et al. (2015)</a> found that mutant mouse embryos expressing Gars(P234KY) initially developed normally, but by embryonic day 13.5, they showed a defect in facial motor neuron migration. After birth, they developed CMT2D-like symptoms, including overt neuromuscular dysfunction and abnormal walking stride, which were accompanied by defects in neuromuscular junctions. <a href="#11" class="mim-tip-reference" title="He, W., Bai, G., Zhou, H., Wei, N., White, N. M., Lauer, J., Liu, H., Shi, Y., Dumitru, C. D., Lettieri, K., Shubayev, V., Jordanova, A., Guergueltcheva, V., Griffin, P. R., Burgess, R. W., Pfaff, S. L., Yang, X.-L. <strong>CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase.</strong> Nature 526: 710-714, 2015. Note: Erratum: Nature 532: 402 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26503042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26503042</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26503042[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/nature15510" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26503042">He et al. (2015)</a> observed that the phenotype was similar to that of Nrp1-null and Vegfa-null mice. Heterozygous knockout of Nrp1 in Gars(P234KY) mutant mice exacerbated the CMT2D symptoms, whereas enhanced expression of VEGF improved motor function. <a href="#11" class="mim-tip-reference" title="He, W., Bai, G., Zhou, H., Wei, N., White, N. M., Lauer, J., Liu, H., Shi, Y., Dumitru, C. D., Lettieri, K., Shubayev, V., Jordanova, A., Guergueltcheva, V., Griffin, P. R., Burgess, R. W., Pfaff, S. L., Yang, X.-L. <strong>CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase.</strong> Nature 526: 710-714, 2015. Note: Erratum: Nature 532: 402 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26503042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26503042</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26503042[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/nature15510" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26503042">He et al. (2015)</a> concluded that the Gars(P234KY) mutant interferes with Nrp1-Vegfa-dependent axon guidance cues during mouse neuronal development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26503042" 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="#23" class="mim-tip-reference" title="Spaulding, E. L., Hines, T. J., Bais, P., Tadenev, A. L. D., Schneider, R., Jewett, D., Pattavina, B., Pratt, S. L., Morelli, K. H., Stum, M. G., Hill, D. P., Gobet, C., and 11 others. <strong>The integrated stress response contributes to tRNA synthetase-associated peripheral neuropathy.</strong> Science 373: 1156-1161, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34516839/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34516839</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34516839[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.abb3414" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34516839">Spaulding et al. (2021)</a> demonstrated impaired protein translation in motor neurons of mice with a dominant mutation in Gars (Gars C201R/+ or Gars P278KY/+). Interestingly, translation was not impaired in the liver or heart. Gene expression studies in the spinal cord motor neurons from the mutant mice demonstrated upregulated genes involved in the integrated stress response (ISR). The mutant mice were bred with Gcn2 (<a href="/entry/609280">609280</a>) homozygous knockout mice, and progression of neuropathy was prevented in the double mutant mice. Mutant Gars mice were also treated with a GCN2 inhibitor, and some improvement in motor performance and sciatic nerve conduction velocity was seen. <a href="#23" class="mim-tip-reference" title="Spaulding, E. L., Hines, T. J., Bais, P., Tadenev, A. L. D., Schneider, R., Jewett, D., Pattavina, B., Pratt, S. L., Morelli, K. H., Stum, M. G., Hill, D. P., Gobet, C., and 11 others. <strong>The integrated stress response contributes to tRNA synthetase-associated peripheral neuropathy.</strong> Science 373: 1156-1161, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34516839/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34516839</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34516839[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.abb3414" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34516839">Spaulding et al. (2021)</a> concluded that mutations in GARS cause neuropathy by activating the ISR in a subset of neurons and that inhibiting GCN2 could be a therapeutic strategy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34516839" 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="#27" class="mim-tip-reference" title="Zuko, A., Mallik, M., Thompson, R., Spaulding, E. L., Wienand, A. R., Been, M., Tadenev, A. L. D., van Bakel, N., Sijlmans, C., Santos, L. A., Bussmann, J., Catinozzi, M., Das, S., Kulshrestha, D., Burgess, R. W., Ignatova, Z., Storkebaum, E. <strong>tRNA overexpression rescues peripheral neuropathy caused by mutations in tRNA synthetase.</strong> Science 373: 1161-1166, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34516840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34516840</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34516840[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.abb3356" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34516840">Zuko et al. (2021)</a> overexpressed tRNA Gly-GCC in mice with a heterozygous C201R mutation in the Gars gene. The overexpression of tRNA Gly-GCC completely prevented peripheral neuropathy in the mutant mice without affecting Gars mRNA and GlyRS protein levels. Furthermore, overexpression of RNA Gly-GCC in mice with a heterozygous delETAQ mutation in the Gars gene abrogated the activation of the integrated stress response in motor neurons that was seen in motor neurons of mice without overexpression of RNA Gly-GCC. This provided evidence that the mutant Gars sequesters tRNA Gly and depletes it for translation, which activates the ISR in motor neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34516840" 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>Zebrafish</em></strong></p><p>
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Using a positional cloning strategy, <a href="#14" class="mim-tip-reference" title="Malissovas, N., Griffin, L. B., Antonellis, A., Beis, D. <strong>Dimerization is required for GARS-mediated neurotoxicity in dominant CMT disease.</strong> Hum. Molec. Genet. 25: 1528-1542, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27008886/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27008886</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27008886[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/10.1093/hmg/ddw031" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27008886">Malissovas et al. (2016)</a> identified a recessive lethal mutation in zebrafish gars, a thr209-to-lys (T209K) substitution equivalent to T130K in human GARS. T209 in zebrafish gars is located inside the catalytic domain at the dimer interface, and the T209K mutation affected gars homodimerization. Yeast complementation assays suggested that T209K is a loss-of-function mutation. In zebrafish larvae, homozygosity for T209K resulted in partial innervation and degeneration of fast muscle fibers in developing skeletal muscle. Loss of gars function prevented formation of functional cardiac valves at later stages of cardiac development. Further analysis confirmed that T209K caused loss of function, as the mutant protein was a monomer and could not catalyze ligation of glycine to its cognate tRNA, thereby impairing protein translation and causing the mutant phenotype in zebrafish. Wildtype zebrafish gars could rescue the neuromuscular phenotype in zebrafish homozygous for T209K, whereas expression of zebrafish gars with a gly319-to-arg (G319R) mutation, equivalent to the human mutation G240R (<a href="#0001">600287.0001</a>) associated with reduced dimerization and aminoacylation, could not rescue the phenotype. Zebrafish gars with another mutation, G605R, equivalent to the human mutation G526R (<a href="#0004">600287.0004</a>) that causes lack of enzymatic activity but retention of dimerization ability, also failed to rescue the phenotype of zebrafish homozygous for T209K. Zebrafish gars with a cys201-to-arg (C201R) mutation, equivalent to C236R in mouse Gars, which is unable to dimerize and partially lacks enzymatic activity, could rescue the phenotype of mutant zebrafish partially. Overexpression analysis in zebrafish heterozygous for T209K showed that dominant toxicity was associated with dimerization of the gars protein, as toxic potential of G605R was reduced when gars-G605R dimerized with gars-T209K. EGFP-tagged human GARS with T130K mislocalized in transfected mouse motor neurons, which was also subsequently confirmed by ectopic expression analysis of gars in zebrafish larvae. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27008886" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>13 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=600287[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137852643 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852643;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/rs137852643?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=rs137852643" 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=rs137852643" 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 families with Charcot-Marie-Tooth disease type 2D (CMT2D; <a href="/entry/601472">601472</a>) first reported by <a href="#12" class="mim-tip-reference" title="Ionasescu, V., Searby, C., Sheffield, V. C., Roklina, T., Nishimura, D., Ionasescu, R. <strong>Autosomal dominant Charcot-Marie-Tooth axonal neuropathy mapped on chromosome 7p (CMT2D).</strong> Hum. Molec. Genet. 5: 1373-1375, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8872480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8872480</a>] [<a href="https://doi.org/10.1093/hmg/5.9.1373" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8872480">Ionasescu et al. (1996)</a> and <a href="#19" class="mim-tip-reference" title="Pericak-Vance, M. A., Speer, M. C., Lennon, F., West, S. G., Menold, M. M., Stajich, J. M., Wolpert, C. M., Slotterbeck, B. D., Saito, M., Tim, R. W., Rozear, M. P., Middleton, L. T., Tsuji, S., Vance, J. M. <strong>Confirmation of a second locus for CMT2 and evidence for additional genetic heterogeneity.</strong> Neurogenetics 1: 89-93, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10732809/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10732809</a>] [<a href="https://doi.org/10.1007/s100480050013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10732809">Pericak-Vance et al. (1997)</a>, <a href="#2" class="mim-tip-reference" title="Antonellis, A., Ellsworth, R. E., Sambuughin, N., Puls, I., Abel, A., Lee-Lin, S.-Q., Jordanova, A., Kremensky, I., Christodoulou, K., Middleton, L. T., Sivakumar, K., Ionasescu, V., Funalot, B., Vance, J. M., Goldfarb, L. G., Fischbeck, K. H., Green, E. D. <strong>Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V.</strong> Am. J. Hum. Genet. 72: 1293-1299, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12690580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12690580</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12690580[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/10.1086/375039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12690580">Antonellis et al. (2003)</a> identified a heterozygous c.1236G-C change in the GARS gene, resulting in a gly240-to-arg (G240R) substitution. The mutation was absent in 368 unrelated chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10732809+12690580+8872480" 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">rs137852644 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852644;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=rs137852644" 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=rs137852644" 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=RCV000009783 OR RCV000857175 OR RCV001310958 OR RCV003332077" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009783, RCV000857175, RCV001310958, RCV003332077" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009783...</a>
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<p>In a family with autosomal dominant distal hereditary motor neuronopathy-5 (HMND5; <a href="/entry/600794">600794</a>) first reported by <a href="#4" class="mim-tip-reference" title="Christodoulou, K., Kyriakides, T., Hristova, A. H., Georgiou, D.-M., Kalaydjieva, L., Yshpekova, B., Ivanova, T., Weber, J. L., Middleton, L. T. <strong>Mapping of a distal form of spinal muscular atrophy with upper limb predominance to chromosome 7p.</strong> Hum. Molec. Genet. 4: 1629-1632, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8541851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8541851</a>] [<a href="https://doi.org/10.1093/hmg/4.9.1629" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8541851">Christodoulou et al. (1995)</a>, <a href="#2" class="mim-tip-reference" title="Antonellis, A., Ellsworth, R. E., Sambuughin, N., Puls, I., Abel, A., Lee-Lin, S.-Q., Jordanova, A., Kremensky, I., Christodoulou, K., Middleton, L. T., Sivakumar, K., Ionasescu, V., Funalot, B., Vance, J. M., Goldfarb, L. G., Fischbeck, K. H., Green, E. D. <strong>Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V.</strong> Am. J. Hum. Genet. 72: 1293-1299, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12690580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12690580</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12690580[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/10.1086/375039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12690580">Antonellis et al. (2003)</a> identified a heterozygous c.904C-T transition in the GARS gene, resulting in a leu129-to-pro (L129P) substitution. The mutation was absent in 376 unrelated chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12690580+8541851" 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">rs137852645 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852645;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=rs137852645" 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=rs137852645" 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=RCV000009784 OR RCV000790253 OR RCV001260976" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009784, RCV000790253, RCV001260976" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009784...</a>
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<p>In a large family in which affected members had either Charcot-Marie-Tooth disease type 2D (CMT2D; <a href="/entry/601472">601472</a>) or autosomal dominant distal hereditary motor neuronopathy-5 (HMND5; <a href="/entry/600794">600794</a>), originally reported by <a href="#20" class="mim-tip-reference" title="Sambuughin, N., Sivakumar, K., Selenge, B., Lee, H. S., Friedlich, D., Baasanjav, D., Dalakas, M. C., Goldfarb, L. G. <strong>Autosomal dominant distal spinal muscular atrophy type V (dSMA-V) and Charcot-Marie-Tooth disease type 2D (CMT2D) segregate within a single large kindred and map to a refined region on chromosome 7p15.</strong> J. Neurol. Sci. 161: 23-28, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9879677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9879677</a>] [<a href="https://doi.org/10.1016/s0022-510x(98)00264-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9879677">Sambuughin et al. (1998)</a>, <a href="#2" class="mim-tip-reference" title="Antonellis, A., Ellsworth, R. E., Sambuughin, N., Puls, I., Abel, A., Lee-Lin, S.-Q., Jordanova, A., Kremensky, I., Christodoulou, K., Middleton, L. T., Sivakumar, K., Ionasescu, V., Funalot, B., Vance, J. M., Goldfarb, L. G., Fischbeck, K. H., Green, E. D. <strong>Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V.</strong> Am. J. Hum. Genet. 72: 1293-1299, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12690580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12690580</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12690580[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/10.1086/375039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12690580">Antonellis et al. (2003)</a> identified a heterozygous c.730A-G mutation in the GARS gene, resulting in a glu71-to-gly (E71G) substitution at a highly conserved residue. The mutation was absent in 398 unrelated chromosomes. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12690580+9879677" 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>Variant Function</em></strong></p><p>
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<a href="#10" class="mim-tip-reference" title="Griffin, L. B., Sakaguchi, R., McGuigan, D., Gonzalez, M. A., Searby, C., Zuchner, S., Hou, Y.-M., Antonellis, A. <strong>Impaired function is a common feature of neuronopathy-associated glycyl-tRNA synthetase mutations.</strong> Hum. Mutat. 35: 1363-1371, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25168514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25168514</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25168514[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.22681" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25168514">Griffin et al. (2014)</a> found that the E71G variant did not impair GARS function in 3 in vitro assays: it had normal enzyme activity; yeast transfected with the variant showed normal growth; and the variant showed normal intracellular localization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25168514" 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 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 5</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">rs137852646 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852646;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=rs137852646" 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=rs137852646" 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=RCV000009786 OR RCV000790258 OR RCV001542258 OR RCV002228024" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009786, RCV000790258, RCV001542258, RCV002228024" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009786...</a>
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<p>In a family with autosomal dominant distal hereditary motor neuronopathy-5 (HMND5; <a href="/entry/600794">600794</a>), <a href="#2" class="mim-tip-reference" title="Antonellis, A., Ellsworth, R. E., Sambuughin, N., Puls, I., Abel, A., Lee-Lin, S.-Q., Jordanova, A., Kremensky, I., Christodoulou, K., Middleton, L. T., Sivakumar, K., Ionasescu, V., Funalot, B., Vance, J. M., Goldfarb, L. G., Fischbeck, K. H., Green, E. D. <strong>Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V.</strong> Am. J. Hum. Genet. 72: 1293-1299, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12690580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12690580</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12690580[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/10.1086/375039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12690580">Antonellis et al. (2003)</a> identified a heterozygous c.2094G-C mutation in exon 14 of the GARS gene, resulting in a gly526-to-arg (G526R) substitution. The mutation was absent in 360 unrelated chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12690580" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Dubourg, O., Azzedine, H., Ben Yaou, R., Pouget, J., Barois, A., Meininger, V., Bouteiller, D., Ruberg, M., Brice, A., LeGuern, E. <strong>The G526R glycyl-tRNA synthetase gene mutation in distal hereditary motor neuropathy type V.</strong> Neurology 66: 1721-1726, 2006. Note: Erratum: Neurology 67: 727 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16769947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16769947</a>] [<a href="https://doi.org/10.1212/01.wnl.0000218304.02715.04" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16769947">Dubourg et al. (2006)</a> identified the G526R mutation in 12 affected members from 3 French families of Sephardic Jewish origin with HMND5. Four mutation carriers were clinically asymptomatic, suggesting incomplete penetrance. Most presented with distal upper limb involvement between the second and fourth decades; none had sensory involvement. Haplotype analysis suggested a founder effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16769947" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2D</strong>
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NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 5, INCLUDED
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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> rs137852647 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852647;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/rs137852647?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=rs137852647" 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=rs137852647" 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=RCV000009787 OR RCV000009788 OR RCV000790257 OR RCV001161100 OR RCV005055510" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009787, RCV000009788, RCV000790257, RCV001161100, RCV005055510" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009787...</a>
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<p>In a large Italian multigenerational family in which affected members had either Charcot-Marie-Tooth disease type 2D (CMT2D; <a href="/entry/601472">601472</a>) or autosomal dominant distal hereditary motor neuronopathy-5 (HMND5; <a href="/entry/600794">600794</a>), <a href="#5" class="mim-tip-reference" title="Del Bo, R., Locatelli, F., Corti, S., Scarlato, M., Ghezzi, S., Prelle, A., Fagiolari, G., Moggio, M., Carpo, M., Bresolin, N., Comi, G. P. <strong>Coexistence of CMT-2D and distal SMA-V phenotypes in an Italian family with a GARS gene mutation.</strong> Neurology 66: 752-754, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16534118/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16534118</a>] [<a href="https://doi.org/10.1212/01.wnl.0000201275.18875.ac" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16534118">Del Bo et al. (2006)</a> identified a heterozygous c.2016G-A transition in exon 13 of the GARS gene, resulting in an asp500-to-asn (D500N) substitution. The mutation was not identified in 100 control Italian individuals. There was broad intrafamilial phenotype variability, with some members presenting symptoms in childhood and some in adulthood. Sensory involvement was variable. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16534118" 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>Variant Function</em></strong></p><p>
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<a href="#10" class="mim-tip-reference" title="Griffin, L. B., Sakaguchi, R., McGuigan, D., Gonzalez, M. A., Searby, C., Zuchner, S., Hou, Y.-M., Antonellis, A. <strong>Impaired function is a common feature of neuronopathy-associated glycyl-tRNA synthetase mutations.</strong> Hum. Mutat. 35: 1363-1371, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25168514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25168514</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25168514[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.22681" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25168514">Griffin et al. (2014)</a> found that the D500N variant did not impair GARS function in 2 in vitro assays: the variant had normal enzyme activity and showed normal intracellular localization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25168514" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2D</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">rs137852648 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852648;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=rs137852648" 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=rs137852648" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a Japanese patient with Charcot-Marie-Tooth disease type 2D (CMT2D; <a href="/entry/601472">601472</a>), <a href="#1" class="mim-tip-reference" title="Abe, A., Hayasaka, K. <strong>The GARS gene is rarely mutated in Japanese patients with Charcot-Marie-Tooth neuropathy.</strong> J. Hum. Genet. 54: 310-312, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19329989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19329989</a>] [<a href="https://doi.org/10.1038/jhg.2009.25" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19329989">Abe and Hayasaka (2009)</a> identified a heterozygous c.893C-T transition in the GARS gene, resulting in a pro244-to-leu (P244L) substitution in the catalytic domain. The mutation was not identified in 100 controls, is conserved among species, and was predicted to alter the secondary structure of the polypeptide. The patient had onset of the disorder in adolescence and early upper-limb involvement. No mutations in the GARS gene were found in 109 additional Japanese patients with axonal CMT, suggesting that GARS mutations are a rare cause of the disorder in this population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19329989" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 SPINAL MUSCULAR ATROPHY, INFANTILE, JAMES TYPE</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> rs747080824 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs747080824;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/rs747080824?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=rs747080824" 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=rs747080824" 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=RCV000789772 OR RCV001260978 OR RCV003447257" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000789772, RCV001260978, RCV003447257" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000789772...</a>
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<p>In a 7-year-old girl, born of unrelated parents (family 1), with the James type of infantile spinal muscular atrophy (SMAJI; <a href="/entry/619042">619042</a>), <a href="#13" class="mim-tip-reference" title="James, P. A., Cader, M. Z., Muntoni, F., Childs, A.-M., Crow, Y. J., Talbot, K. <strong>Severe childhood SMA and axonal CMT due to anticodon binding domain mutations in the GARS gene.</strong> Neurology 67: 1710-1712, 2006. Note: Erratum: Neurology 68: 711 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17101916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17101916</a>] [<a href="https://doi.org/10.1212/01.wnl.0000242619.52335.bc" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17101916">James et al. (2006)</a> identified a de novo heterozygous c.2313G-C transversion in the GARS1 gene, resulting in a gly598-to-ala (G598A) substitution in the center of the anticodon binding domain. Functional studies of the variant were not performed, but the authors postulated a dominant-negative effect. The patient presented at 6 months of age with lower extremity weakness and did not achieve independent ambulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17101916" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a pair of monozygotic twin girls with SMAJI, <a href="#7" class="mim-tip-reference" title="Eskuri, J. M., Stanley, C. M., Moore, S. A., Mathews, K. D. <strong>Infantile onset CMT2D/dSMA V in monozygotic twins due to a mutation in the anticodon-binding domain of GARS.</strong> J. Peripher. Nerv. Syst. 17: 132-134, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22462675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22462675</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22462675[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/10.1111/j.1529-8027.2012.00370.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22462675">Eskuri et al. (2012)</a> identified a de novo heterozygous c.1955G-C transversion in the GARS1 gene, resulting in a gly652-to-ala (G652A) substitution, which the authors stated was the same mutation as that reported by <a href="#13" class="mim-tip-reference" title="James, P. A., Cader, M. Z., Muntoni, F., Childs, A.-M., Crow, Y. J., Talbot, K. <strong>Severe childhood SMA and axonal CMT due to anticodon binding domain mutations in the GARS gene.</strong> Neurology 67: 1710-1712, 2006. Note: Erratum: Neurology 68: 711 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17101916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17101916</a>] [<a href="https://doi.org/10.1212/01.wnl.0000242619.52335.bc" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17101916">James et al. (2006)</a>. Functional studies of the variant were not performed, but the patients had a similar phenotype as the girl reported by <a href="#13" class="mim-tip-reference" title="James, P. A., Cader, M. Z., Muntoni, F., Childs, A.-M., Crow, Y. J., Talbot, K. <strong>Severe childhood SMA and axonal CMT due to anticodon binding domain mutations in the GARS gene.</strong> Neurology 67: 1710-1712, 2006. Note: Erratum: Neurology 68: 711 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17101916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17101916</a>] [<a href="https://doi.org/10.1212/01.wnl.0000242619.52335.bc" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17101916">James et al. (2006)</a>. The findings suggested that mutations in the anticodon binding domain may result in a severe phenotype with infantile onset. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17101916+22462675" 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>Variant Function</em></strong></p><p>
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Using in vitro studies, <a href="#10" class="mim-tip-reference" title="Griffin, L. B., Sakaguchi, R., McGuigan, D., Gonzalez, M. A., Searby, C., Zuchner, S., Hou, Y.-M., Antonellis, A. <strong>Impaired function is a common feature of neuronopathy-associated glycyl-tRNA synthetase mutations.</strong> Hum. Mutat. 35: 1363-1371, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25168514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25168514</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25168514[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.22681" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25168514">Griffin et al. (2014)</a> demonstrated that the G598A mutation had less than 10% aminoacylation activity compared to wildtype. The G598A mutant protein did not associate normally with puncta in a neuroblastoma cell line, suggesting that reduced localization to axons may be a component of the pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25168514" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 5</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> rs768987322 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs768987322;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/rs768987322?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=rs768987322" 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=rs768987322" 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=RCV000857176 OR RCV001253591 OR RCV001260979 OR RCV003482320 OR RCV004768719 OR RCV005092541" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000857176, RCV001253591, RCV001260979, RCV003482320, RCV004768719, RCV005092541" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000857176...</a>
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<p>In a patient (patient 1) and his mother with autosomal dominant distal hereditary motor neuronopathy-5 (HMND5; <a href="/entry/600794">600794</a>), <a href="#3" class="mim-tip-reference" title="Boczonadi, V., Meyer, K., Gonczarowska-Jorge, H., Griffin, H., Roos, A., Bartsakoulia, M., Bansagi, B., Ricci, G., Palinkas, F., Zahedi, R. P., Bruni, F., Kaspar, B., Lochmuller, H., Boycott, K. M., Muller, J. S., Horvath, R. <strong>Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons.</strong> Hum. Molec. Genet. 27: 2187-2204, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29648643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29648643</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29648643[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/10.1093/hmg/ddy127" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29648643">Boczonadi et al. (2018)</a> identified a heterozygous c.647A-G transition in the GARS1 gene, resulting in a his216-to-arg (H216R) substitution. The mutation was identified through sequencing of a gene panel. Patient fibroblasts did not show a defect in mitochondrial translation, but detailed studies on induced neuronal progenitor cells derived from patient fibroblasts showed decreased levels of mitochondrial respiratory chain complexes, impaired mitochondrial respiration and metabolism, defects in calcium flux dynamics, and increased autophagic vacuoles. These findings were consistent with tissue-specific effects of the mutation; the authors postulated a dominant gain-of-function mechanism. The patients had onset of upper limb-predominant distal neuropathy in their early twenties. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29648643" 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">rs797044855 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797044855;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=rs797044855" 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=rs797044855" 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=RCV000190657 OR RCV001260977" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000190657, RCV001260977" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000190657...</a>
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<p>In a 14-month-old infant (patient 2) with the James type of infantile spinal muscular atrophy (SMAJI; <a href="/entry/619042">619042</a>), <a href="#8" class="mim-tip-reference" title="Forrester, N., Rattihalli, R., Horvath, R., Maggi, L., Manzur, A., Fuller, G., Gutowski, N., Rankin, J., Dick, D., Buxton, C., Greenslade, M., Majumdar, A. <strong>Clinical and genetic features in a series of eight unrelated patients with neuropathy due to glycyl-tRNA synthetase (GARS) variants.</strong> J. Neuromusc. Dis. 7: 137-143, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31985473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31985473</a>] [<a href="https://doi.org/10.3233/JND-200472" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31985473">Forrester et al. (2020)</a> identified a heterozygous c.373G-A transition (c.373G-A, NM_002047.2) in the GARS1 gene, resulting in a glu125-to-lys (E125K) substitution. The mutation was found by next-generation sequencing and confirmed by Sanger sequencing; functional studies and studies of patient cells were not performed. There was no mention of family history, segregation of the mutation, or genetic testing of the parents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31985473" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 unrelated children (patients 1 and 2), both of Hispanic descent, with the James type of infantile spinal muscular atrophy (SMAJI; <a href="/entry/619042">619042</a>), <a href="#15" class="mim-tip-reference" title="Markovitz, R., Ghosh, R., Kuo, M. E., Hong, W., Lim, J., Bernes, S., Manberg, S., Crosby, K., Tanpaiboon, P., Bharucha-Goebel, D., Bonnemann, C., Mohila, C. A., Mizerik, E., Woodbury, S., Bi, W., Lotze, T., Antonellis, A., Xiao, R., Potocki, L. GARS-related disease in infantile spinal muscular atrophy. <strong>implications for diagnosis and treatment.</strong> Am. J. Med. Genet. 182A: 1167-1176, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32181591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32181591</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32181591[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.61544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32181591">Markovitz et al. (2020)</a> identified a de novo heterozygous c.1001T-A transversion (c.1001T-A, NM_002047.2) in the GARS1 gene, resulting in an ile334-to-asn (I334N) substitution at a highly conserved residue in the catalytic domain. The mutation, which found by trio-based exome sequencing, was not present in the gnomAD database. In vitro functional complementation studies showed that the I334N variant was unable to rescue the growth defect phenotype in yeast with deletion of this ortholog, consistent with a loss-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32181591" 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">rs1783251037 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1783251037;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=rs1783251037" 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=rs1783251037" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 14-month-old infant (patient 3) with the James type of infantile spinal muscular atrophy (SMAJI; <a href="/entry/619042">619042</a>), <a href="#15" class="mim-tip-reference" title="Markovitz, R., Ghosh, R., Kuo, M. E., Hong, W., Lim, J., Bernes, S., Manberg, S., Crosby, K., Tanpaiboon, P., Bharucha-Goebel, D., Bonnemann, C., Mohila, C. A., Mizerik, E., Woodbury, S., Bi, W., Lotze, T., Antonellis, A., Xiao, R., Potocki, L. GARS-related disease in infantile spinal muscular atrophy. <strong>implications for diagnosis and treatment.</strong> Am. J. Med. Genet. 182A: 1167-1176, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32181591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32181591</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32181591[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.61544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32181591">Markovitz et al. (2020)</a> identified a de novo heterozygous c.1954G-C transversion (c.1954G-C, NM_002047.2) in the GARS1 gene, resulting in a gly652-to-arg (G652R) substitution at a highly conserved residue in the anticodon binding domain. The mutation, which found by trio-based exome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. The affected residue was the same as that identified in other patients with a similar phenotype (<a href="#0007">600287.0007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32181591" 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">rs1554337974 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1554337974;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=rs1554337974" 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=rs1554337974" 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 Malian sibs, aged 19 and 35 years, with axonal Charcot-Marie-Tooth disease type 2D (CMT2D; <a href="/entry/601472">601472</a>), who were born to consanguineous parents of Bambara ethnicity, <a href="#26" class="mim-tip-reference" title="Yalcouye, A., Diallo, S. H., Coulibaly, T., Cisse, L., Diallo, S., Samassekou, O., Diarra, S., Coulibaly, D., Keita, M., Guinto, C. O., Fischbeck, K., Landoure, G., The H3Africa Consortium. <strong>A novel mutation in the GARS gene in a Malian family with Charcot-Marie-Tooth disease.</strong> Molec. Genet. Genomic Med. 7: e782, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31173493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31173493</a>] [<a href="https://doi.org/10.1002/mgg3.782" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31173493">Yalcouye et al. (2019)</a> identified a c.794C-A transversion in the GARS1 gene, resulting in a ser265-to-tyr (S265Y) substitution in a conserved region of the protein. The patients' mother also had the mutation but was asymptomatic, suggesting incomplete penetrance. The mutation was identified by next-generation sequencing of a panel of 50 genes associated with CMT. The variant was not found in the ExAC, dbSNP, or 1000 Genomes Project databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31173493" 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>.0013 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 5</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">rs1060502838 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1060502838;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=rs1060502838" 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=rs1060502838" 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=RCV000459084 OR RCV000664213 OR RCV000789777 OR RCV000790256 OR RCV003332179 OR RCV004022757" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000459084, RCV000664213, RCV000789777, RCV000790256, RCV003332179, RCV004022757" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000459084...</a>
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<p>In 3 affected members of a large multigenerational family with autosomal dominant distal hereditary motor neuronopathy-5 (HMND5; <a href="/entry/600794">600794</a>), <a href="#8" class="mim-tip-reference" title="Forrester, N., Rattihalli, R., Horvath, R., Maggi, L., Manzur, A., Fuller, G., Gutowski, N., Rankin, J., Dick, D., Buxton, C., Greenslade, M., Majumdar, A. <strong>Clinical and genetic features in a series of eight unrelated patients with neuropathy due to glycyl-tRNA synthetase (GARS) variants.</strong> J. Neuromusc. Dis. 7: 137-143, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31985473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31985473</a>] [<a href="https://doi.org/10.3233/JND-200472" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31985473">Forrester et al. (2020)</a> identified a heterozygous c.1415A-G transition (c.1415A-G, NM_002047.2) in the GARS1 gene, resulting in a his472-to-arg (H472R) substitution. An unrelated patient (patient 6) with the disorder also carried the mutation. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Functional studies of the variant and studies of patient cells were not performed, but it was classified as pathogenic by ACMG criteria. <a href="#8" class="mim-tip-reference" title="Forrester, N., Rattihalli, R., Horvath, R., Maggi, L., Manzur, A., Fuller, G., Gutowski, N., Rankin, J., Dick, D., Buxton, C., Greenslade, M., Majumdar, A. <strong>Clinical and genetic features in a series of eight unrelated patients with neuropathy due to glycyl-tRNA synthetase (GARS) variants.</strong> J. Neuromusc. Dis. 7: 137-143, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31985473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31985473</a>] [<a href="https://doi.org/10.3233/JND-200472" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31985473">Forrester et al. (2020)</a> noted that <a href="#10" class="mim-tip-reference" title="Griffin, L. B., Sakaguchi, R., McGuigan, D., Gonzalez, M. A., Searby, C., Zuchner, S., Hou, Y.-M., Antonellis, A. <strong>Impaired function is a common feature of neuronopathy-associated glycyl-tRNA synthetase mutations.</strong> Hum. Mutat. 35: 1363-1371, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25168514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25168514</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25168514[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.22681" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25168514">Griffin et al. (2014)</a> found that the H472R variant reduced aminoacyl-tRNA synthetase activity to 6.25% compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=31985473+25168514" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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[<a href="https://doi.org/10.1038/jhg.2009.25" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddy127" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/4.9.1629" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000201275.18875.ac" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000218304.02715.04" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1529-8027.2012.00370.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1186/1471-2350-15-36" target="_blank">Full Text</a>]
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<strong>Localization of two human autoantigen genes by PCR screening and in situ hybridization--Glycyl-tRNA synthetase locates to 7p15 and alanyl-tRNA synthetase locates to 16q22.</strong>
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[<a href="https://doi.org/10.1006/geno.1995.0028" target="_blank">Full Text</a>]
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<a id="Oprescu2017" class="mim-anchor"></a>
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Oprescu, S. N., Chepa-Lotrea, X., Takase, R., Golas, G., Markello, T. C., Adams, D. R., Toro, C., Gropman, A. L., Hou, Y.-M., Malicdan, M. C. V., Gahl, W. A., Tifft, C. J., Antonellis, A.
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[<a href="https://doi.org/10.1002/humu.23287" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s100480050013" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0022-510x(98)00264-0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.neuron.2006.08.027" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/nar/23.8.1307" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/mgg3.782" target="_blank">Full Text</a>]
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Zuko, A., Mallik, M., Thompson, R., Spaulding, E. L., Wienand, A. R., Been, M., Tadenev, A. L. D., van Bakel, N., Sijlmans, C., Santos, L. A., Bussmann, J., Catinozzi, M., Das, S., Kulshrestha, D., Burgess, R. W., Ignatova, Z., Storkebaum, E.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34516840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34516840</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34516840[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=34516840" 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.abb3356" target="_blank">Full Text</a>]
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Bao Lige - updated : 04/04/2022<br>Cassandra L. Kniffin - updated : 12/01/2020<br>Hilary J. Vernon - updated : 11/16/2020<br>Cassandra L. Kniffin - updated : 10/08/2020<br>Patricia A. Hartz - updated : 07/19/2016<br>Patricia A. Hartz - updated : 07/19/2016<br>Patricia A. Hartz - updated : 07/19/2016<br>Cassandra L. Kniffin - updated : 2/23/2015<br>Cassandra L. Kniffin - updated : 11/30/2009<br>Cassandra L. Kniffin - updated : 6/23/2009<br>Cassandra L. Kniffin - updated : 9/18/2007<br>Cassandra L. Kniffin - updated : 6/12/2007<br>Cassandra L. Kniffin - updated : 4/17/2003<br>Alan F. Scott - updated : 2/12/1996<br>Alan F. Scott - updated : 9/20/1995
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<h3>
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<span class="mim-font">
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GLYCYL-tRNA SYNTHETASE 1; GARS1
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</span>
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</h3>
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</div>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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<div>
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<h4>
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<span class="mim-font">
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GARS
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: GARS1</em></strong>
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</span>
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</p>
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</div>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 1197152005, 717011006;
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<strong>
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<em>
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Cytogenetic location: 7p14.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 7:30,594,735-30,634,033 </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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<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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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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</thead>
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<tbody>
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<tr>
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<td rowspan="3">
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<span class="mim-font">
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7p14.3
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</span>
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</td>
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<td>
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<span class="mim-font">
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Charcot-Marie-Tooth disease, type 2D
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</td>
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<td>
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<span class="mim-font">
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601472
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</span>
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<td>
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<span class="mim-font">
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Autosomal dominant
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<td>
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<span class="mim-font">
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3
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</td>
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<tr>
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<td>
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<span class="mim-font">
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Neuronopathy, distal hereditary motor, autosomal dominant 5
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</span>
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</td>
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<td>
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<span class="mim-font">
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600794
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<span class="mim-font">
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Autosomal dominant
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<td>
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<span class="mim-font">
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3
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<tr>
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<td>
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<span class="mim-font">
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Spinal muscular atrophy, infantile, James type
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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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619042
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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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</tbody>
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</table>
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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 GARS1 gene encodes glycyl-tRNA synthetase, an enzyme that is responsible for covalently attaching glycine to its cognate tRNA, which is essential for protein translation. Unlike most other tRNA synthetase genes, GARS1 encodes both the cytoplasmic and mitochondrial isoforms of the enzyme. The mitochondrial isoform contains a mitochondrial targeting signal (MTS) (summary by Boczonadi et al., 2018). </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>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>Aminoacyl-tRNA synthetases perform an essential function in protein synthesis by catalyzing the esterification of an amino acid to its cognate tRNA. These enzymes are necessarily present in each cell and must properly recognize the tRNA and the amino acid in order to maintain fidelity of translation. From the primary structures, 2 distinct classes of synthetases have been recognized, with similarity of certain structural features, amino acid attachment sites, and other properties between members of a class. Certain aminoacyl-tRNA synthetases are autoantigens in patients with the idiopathic inflammatory myopathies, polymyositis, and dermatomyositis. Autoantibodies reactive with synthetases are found almost exclusively in these conditions, with individuals usually having autoantibodies to only a single synthetase. Most commonly they are directed at histidyl-tRNA synthetase (142810), labeled 'anti-Jo-1' autoantibodies. Ge et al. (1994) used a cDNA encoding the human form of glycyl-tRNA synthetase for isolation of corresponding cDNAs. Shiba et al. (1994) likewise cloned a class II human glycyl-tRNA synthetase and compared its structure with that of the bacterial counterpart from which it was found to diverge widely. </p><p>Williams et al. (1995) also cloned the human GARS cDNA. The predicted 685-amino acid protein showed approximately 45% identity to the yeast protein. The recombinantly expressed protein was immunoprecipitated with human serum containing autoantibodies to glycyl-tRNA synthetase and was shown to catalyze the aminoacylation of tRNA. </p>
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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>Boczonadi et al. (2018) demonstrated that GARS1 localizes to mitochondrial RNA granules in human fibroblasts and oligodendroglial cells, indicating that it likely plays a role in mitochondrial translation. siRNA-mediated knockdown of the GARS1 gene resulted in reduced mitochondrial translation and decreased protein levels of respiratory chain subunits in oligodendroglial cells and myoblasts, but not in fibroblasts, suggesting tissue-specific functions. Detailed functional studies also suggested that GARS1 may have a noncanonical role in calcium metabolism, endoplasmic reticulum (ER) interactions, vesicle dynamics, and autophagy. </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>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>Nichols et al. (1995) mapped the GARS gene to chromosome 7p15 by FISH analysis. </p><p>Stumpf (2020) mapped the GARS1 gene to chromosome 17p14.3 based on an alignment of the GARS1 sequence (GenBank BC007755) with the genomic sequence (GRCh38).</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Charcot-Marie-Tooth Disease Type 2D</em></strong></p><p>
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Antonellis et al. (2003) identified heterozygous mutations in the GARS1 gene (e.g., 600287.0001) in families with Charcot-Marie-Tooth disease type 2D (CMT2D; 601472). </p><p>In 2 Malian sibs with CMT2D, Yalcouye et al. (2019) identified a heterozygous mutation in the GARS1 gene (S265Y; 600287.0012) by next-generation sequencing of a panel of 50 genes associated with CMT. The patients' mother also had the mutation but was asymptomatic, suggesting variable penetrance. </p><p><strong><em>Distal Hereditary Motor Neuronopathy 5, Autosomal Dominant</em></strong></p><p>
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Antonellis et al. (2003) identified heterozygous mutations in the GARS1 gene (e.g., 600287.0002) in families with autosomal dominant distal hereditary motor neuronopathy-5 (HMND5; 600794). </p><p>In a patient (patient 1) and his mother with HMND5, Boczonadi et al. (2018) identified a heterozygous missense mutation in the GARS1 gene (H216R; 600287.0008). The mutation was identified through sequencing of a gene panel. Patient fibroblasts did not show a defect in mitochondrial translation, but detailed studies on induced neuronal progenitor cells derived from patient fibroblasts showed decreased levels of mitochondrial respiratory chain complexes, impaired mitochondrial respiration and metabolism, defects in calcium flux dynamics, and increased autophagic vacuoles. These findings were consistent with tissue-specific effects of the mutation; the authors postulated a dominant gain-of-function mechanism. The patients had onset of upper limb-predominant distal neuropathy in their early twenties. </p><p>In 7 unrelated patients with HMND5, Forrester et al. (2020) identified heterozygous missense variants in the GARS1 gene (see, e.g., H472R, 600287.0013). The variants, which were found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in affected family members of 6 probands, whereas it occurred de novo in 1 patient. Although functional studies of the variants were not performed, 3 (H216R, G327R, and H472R) were classified as pathogenic or likely pathogenic, and 3 were considered to be of uncertain pathogenic significance (R27P, K510Q, and M555V), according to ACMG criteria. </p><p><strong><em>Infantile Spinal Muscular Atrophy, James Type</em></strong></p><p>
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In a 7-year-old girl, born of unrelated parents (family 1), with the James type of infantile spinal muscular atrophy (SMAJI; 619042), James et al. (2006) identified a de novo heterozygous missense mutation in the GARS1 gene (G598A; 600287.0007). Functional studies of the variant were not performed. The patient presented at 6 months of age with lower extremity weakness and did not achieve independent ambulation. </p><p>In a 14-month-old infant (patient 2) with SMAJI, Forrester et al. (2020) identified a heterozygous missense mutation in the GARS1 gene (E125K; 600287.0009). The mutation was found by next-generation sequencing and confirmed by Sanger sequencing; functional studies and studies of patient cells were not performed. </p><p>In 3 unrelated children with SMAJI, Markovitz et al. (2020) identified de novo heterozygous missense mutations in the GARS1 gene (I334N, 600287.0010 and G652R, 600287.0011). The mutations, which were found by trio-based exome sequencing, were not present in the gnomAD database. In vitro functional complementation studies showed that the I334N variant was unable to rescue the growth defect phenotype in yeast, consistent with a loss-of-function effect. Functional studies of the G652R variant were not performed. </p><p><strong><em>Variant Function</em></strong></p><p>
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Griffin et al. (2014) demonstrated that several missense mutations in the GARS gene previously associated with CMT2D and/or HMND5 had less than 10% aminoacylation activity compared to wildtype. These pathogenic mutations included G240R (600287.0001), G526R (600287.0004), D146N, S211F, P244L (600287.0006), I280F, H418R, and G598A (600287.0007). A57V retained about 50% residual activity. Site-directed mutagenesis studies in yeast showed that the D146N and P244L mutations resulted in a severe reduction in cell growth compared to wildtype. Finally, the S211F, P244L, I280F, and G598A mutant proteins did not associate normally with puncta in a neuroblastoma cell line, suggesting that reduced localization to axons may be a component of CMT2D and HMND5 pathogenesis. The findings were consistent with some of the mutations causing a loss of GARS function. However, the E71G (600287.0003) and D500N (600287.0005) mutations did not show impaired function in any of the assays used in the study. </p><p>He et al. (2015) determined that several mutations in the GARS gene that cause CMT2D, including G240R (600287.0001), L129P (600287.0002), and E71G (600287.0003), as well as a pro234-to-lys-tyr (P234KY) substitution in mouse, open a new protein-interaction surface on mutant GARS protein. Using in vitro protein pull-down and coimmunoprecipitation assays, the authors found that GARS(P234KY), GARS(L129P), GARS(G240R), and GARS(E71G) but not wildtype GARS, bound to NRP1 (602069), a VEGFA (192240) receptor required for motor neuron axon guidance and cell body migration. NRP1 coprecipitated GARS(P234KY) from mutant mice and GARS(L129P) in human lymphocytes much more readily than wildtype GARS. GARS(P234KY), but not wildtype GARS, competed with VEGFA for binding the extracellular b1 domain of NRP1. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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McMillan et al. (2014) reported a 12-year-old girl, born of unrelated parents, with evidence of a systemic mitochondrial disorder. Exome sequencing identified compound heterozygous missense variants in the GARS1 gene (S635L and R596Q). Both variants occurred at highly conserved residues in the anticodon binding domain. The variants segregated with the disorder in the family: the unaffected mother carried the R596Q variant, whereas the father, who had a mild sensorimotor polyneuropathy, carried S635L. In addition, the proband carried a heterozygous variant in the MIB1 gene (608677), which is associated with left ventricular noncompaction-7 (LVNC7; 615092), which may have contributed to her cardiomyopathy. However, the MIB1 variant was also present in her father, who did not have cardiac disease. The patient had evidence of a systemic mitochondrial disorder, with exercise-induced myalgia, increased serum lactate and alanine, white matter abnormalities on brain imaging, and cardiomyopathy. Functional studies of the variants and studies of patient cells were not performed. </p><p>Boczonadi et al. (2018) performed functional studies of cells derived from the girl (patient 2) and her father (carrier 2) reported by McMillan et al. (2014). Although patient fibroblasts did not show a mitochondrial translation defect, induced neural progenitor cells derived from patient fibroblasts showed decreased levels of respiratory complex I subunit NDUFB8 (602140), as well as subtle defects in mitochondrial metabolism and fatty acid-beta oxidation. The authors postulated that recessive GARS1 variants may result in a loss-of-function effect with tissue-specific manifestations. </p><p>Oprescu et al. (2017) reported a 7-year-old girl (UDP5316), born of unrelated Caucasian parents, with a severe multisystem developmental disorder. Exome sequencing identified 2 variants in the GARS1 gene: a 4-bp deletion (c.246_249del), resulting in a frameshift and premature termination (Glu83IlefsTer6), and R310Q, which affected a conserved residue in the catalytic domain. Each unaffected parent carried 1 of the variants; neither variant was present in the gnomAD database. In vitro functional studies showed that both variants resulted in a loss-of-function effect on GARS1 activity. The patient was born at 36 weeks' gestation by cesarean section due to intrauterine growth retardation. She showed failure to thrive and global developmental delay, with independent walking at 6 years, pincer grasp at 5 years, and language delay with poor intelligibility. At age 3 years, she was microcephalic with abnormal skull shape and patent anterior fontanel. Dysmorphic features included sparse thin hair, triangular face with broad forehead, epicanthal folds, hypotelorism, smooth philtrum, and high-arched palate. She had upper motor neuron signs with hyperreflexia and spasticity of the lower limbs, but no evidence of lower motor neuron dysfunction or neuropathy. Sensation was normal. Additional features included retinal changes with depigmentation, sensorineural hearing loss, atrial septal defect, pulmonic stenosis, sleep apnea, atopic dermatitis, recurrent rhinitis, and fused cervical vertebrae. Brain imaging showed thin corpus callosum, mild atrophy of the cerebellar vermis, small brainstem, delayed myelination, and enlarged ventricles. Skeletal muscle biopsy was not performed. </p>
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</span>
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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>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Mouse</em></strong></p><p>
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Using positional cloning, Seburn et al. (2006) found that a mutagenesis-induced dominant mouse model Nmf249 was caused by an in-frame indel mutation at pro278 in the Gars gene. Affected mice had a sensorimotor polyneuropathy with overt neuromuscular dysfunction by 3 weeks of age, smaller size, and shortened life spans compared to wildtype mice. Mutant mice showed neurodegenerative changes at the neuromuscular junction, with more severe changes at distal muscles. Nerve conduction velocities were severely decreased, and peripheral nerves showed reduced axonal diameters and loss of large-diameter axons, but no evidence of demyelination. Homozygous mutant mice were embryonic lethal. The affected pro278 residue is near the catalytic domain-2 of the protein, but the mutation did not affect Gars mRNA levels, and the recombinant mutant enzyme showed normal kinetics and activity. The findings were not consistent with either loss of function (haploinsufficiency) or a dominant-negative loss-of-function effect, but Seburn et al. (2006) postulated aberrant pathogenic function of the mutant protein. </p><p>He et al. (2015) found that mutant mouse embryos expressing Gars(P234KY) initially developed normally, but by embryonic day 13.5, they showed a defect in facial motor neuron migration. After birth, they developed CMT2D-like symptoms, including overt neuromuscular dysfunction and abnormal walking stride, which were accompanied by defects in neuromuscular junctions. He et al. (2015) observed that the phenotype was similar to that of Nrp1-null and Vegfa-null mice. Heterozygous knockout of Nrp1 in Gars(P234KY) mutant mice exacerbated the CMT2D symptoms, whereas enhanced expression of VEGF improved motor function. He et al. (2015) concluded that the Gars(P234KY) mutant interferes with Nrp1-Vegfa-dependent axon guidance cues during mouse neuronal development. </p><p>Spaulding et al. (2021) demonstrated impaired protein translation in motor neurons of mice with a dominant mutation in Gars (Gars C201R/+ or Gars P278KY/+). Interestingly, translation was not impaired in the liver or heart. Gene expression studies in the spinal cord motor neurons from the mutant mice demonstrated upregulated genes involved in the integrated stress response (ISR). The mutant mice were bred with Gcn2 (609280) homozygous knockout mice, and progression of neuropathy was prevented in the double mutant mice. Mutant Gars mice were also treated with a GCN2 inhibitor, and some improvement in motor performance and sciatic nerve conduction velocity was seen. Spaulding et al. (2021) concluded that mutations in GARS cause neuropathy by activating the ISR in a subset of neurons and that inhibiting GCN2 could be a therapeutic strategy. </p><p>Zuko et al. (2021) overexpressed tRNA Gly-GCC in mice with a heterozygous C201R mutation in the Gars gene. The overexpression of tRNA Gly-GCC completely prevented peripheral neuropathy in the mutant mice without affecting Gars mRNA and GlyRS protein levels. Furthermore, overexpression of RNA Gly-GCC in mice with a heterozygous delETAQ mutation in the Gars gene abrogated the activation of the integrated stress response in motor neurons that was seen in motor neurons of mice without overexpression of RNA Gly-GCC. This provided evidence that the mutant Gars sequesters tRNA Gly and depletes it for translation, which activates the ISR in motor neurons. </p><p><strong><em>Zebrafish</em></strong></p><p>
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Using a positional cloning strategy, Malissovas et al. (2016) identified a recessive lethal mutation in zebrafish gars, a thr209-to-lys (T209K) substitution equivalent to T130K in human GARS. T209 in zebrafish gars is located inside the catalytic domain at the dimer interface, and the T209K mutation affected gars homodimerization. Yeast complementation assays suggested that T209K is a loss-of-function mutation. In zebrafish larvae, homozygosity for T209K resulted in partial innervation and degeneration of fast muscle fibers in developing skeletal muscle. Loss of gars function prevented formation of functional cardiac valves at later stages of cardiac development. Further analysis confirmed that T209K caused loss of function, as the mutant protein was a monomer and could not catalyze ligation of glycine to its cognate tRNA, thereby impairing protein translation and causing the mutant phenotype in zebrafish. Wildtype zebrafish gars could rescue the neuromuscular phenotype in zebrafish homozygous for T209K, whereas expression of zebrafish gars with a gly319-to-arg (G319R) mutation, equivalent to the human mutation G240R (600287.0001) associated with reduced dimerization and aminoacylation, could not rescue the phenotype. Zebrafish gars with another mutation, G605R, equivalent to the human mutation G526R (600287.0004) that causes lack of enzymatic activity but retention of dimerization ability, also failed to rescue the phenotype of zebrafish homozygous for T209K. Zebrafish gars with a cys201-to-arg (C201R) mutation, equivalent to C236R in mouse Gars, which is unable to dimerize and partially lacks enzymatic activity, could rescue the phenotype of mutant zebrafish partially. Overexpression analysis in zebrafish heterozygous for T209K showed that dominant toxicity was associated with dimerization of the gars protein, as toxic potential of G605R was reduced when gars-G605R dimerized with gars-T209K. EGFP-tagged human GARS with T130K mislocalized in transfected mouse motor neurons, which was also subsequently confirmed by ectopic expression analysis of gars in zebrafish larvae. </p>
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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>ALLELIC VARIANTS</strong>
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</span>
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<strong>13 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2D</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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GARS1, GLY240ARG
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<br />
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|
|
SNP: rs137852643,
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|
|
|
|
|
gnomAD: rs137852643,
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|
|
ClinVar: RCV000009782, RCV000327196, RCV000692132, RCV000789142, RCV004018608
|
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|
|
</span>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In 2 families with Charcot-Marie-Tooth disease type 2D (CMT2D; 601472) first reported by Ionasescu et al. (1996) and Pericak-Vance et al. (1997), Antonellis et al. (2003) identified a heterozygous c.1236G-C change in the GARS gene, resulting in a gly240-to-arg (G240R) substitution. The mutation was absent in 368 unrelated chromosomes. </p>
|
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</span>
|
|
</div>
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<div>
|
|
<br />
|
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</div>
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</div>
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|
<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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GARS1, LEU129PRO
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<br />
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|
SNP: rs137852644,
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|
|
ClinVar: RCV000009783, RCV000857175, RCV001310958, RCV003332077
|
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|
|
|
</span>
|
|
</div>
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|
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a family with autosomal dominant distal hereditary motor neuronopathy-5 (HMND5; 600794) first reported by Christodoulou et al. (1995), Antonellis et al. (2003) identified a heterozygous c.904C-T transition in the GARS gene, resulting in a leu129-to-pro (L129P) substitution. The mutation was absent in 376 unrelated chromosomes. </p>
|
|
</span>
|
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</div>
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<div>
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|
<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2D</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 5, INCLUDED
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
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|
|
|
GARS1, GLU71GLY
|
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|
<br />
|
|
|
|
SNP: rs137852645,
|
|
|
|
|
|
|
|
ClinVar: RCV000009784, RCV000790253, RCV001260976
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a large family in which affected members had either Charcot-Marie-Tooth disease type 2D (CMT2D; 601472) or autosomal dominant distal hereditary motor neuronopathy-5 (HMND5; 600794), originally reported by Sambuughin et al. (1998), Antonellis et al. (2003) identified a heterozygous c.730A-G mutation in the GARS gene, resulting in a glu71-to-gly (E71G) substitution at a highly conserved residue. The mutation was absent in 398 unrelated chromosomes. Functional studies of the variant were not performed. </p><p><strong><em>Variant Function</em></strong></p><p>
|
|
Griffin et al. (2014) found that the E71G variant did not impair GARS function in 3 in vitro assays: it had normal enzyme activity; yeast transfected with the variant showed normal growth; and the variant showed normal intracellular localization. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GARS1, GLY526ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852646,
|
|
|
|
|
|
|
|
ClinVar: RCV000009786, RCV000790258, RCV001542258, RCV002228024
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family with autosomal dominant distal hereditary motor neuronopathy-5 (HMND5; 600794), Antonellis et al. (2003) identified a heterozygous c.2094G-C mutation in exon 14 of the GARS gene, resulting in a gly526-to-arg (G526R) substitution. The mutation was absent in 360 unrelated chromosomes. </p><p>Dubourg et al. (2006) identified the G526R mutation in 12 affected members from 3 French families of Sephardic Jewish origin with HMND5. Four mutation carriers were clinically asymptomatic, suggesting incomplete penetrance. Most presented with distal upper limb involvement between the second and fourth decades; none had sensory involvement. Haplotype analysis suggested a founder effect. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2D</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 5, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GARS1, ASP500ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852647,
|
|
|
|
|
|
gnomAD: rs137852647,
|
|
|
|
|
|
ClinVar: RCV000009787, RCV000009788, RCV000790257, RCV001161100, RCV005055510
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a large Italian multigenerational family in which affected members had either Charcot-Marie-Tooth disease type 2D (CMT2D; 601472) or autosomal dominant distal hereditary motor neuronopathy-5 (HMND5; 600794), Del Bo et al. (2006) identified a heterozygous c.2016G-A transition in exon 13 of the GARS gene, resulting in an asp500-to-asn (D500N) substitution. The mutation was not identified in 100 control Italian individuals. There was broad intrafamilial phenotype variability, with some members presenting symptoms in childhood and some in adulthood. Sensory involvement was variable. Functional studies of the variant were not performed. </p><p><strong><em>Variant Function</em></strong></p><p>
|
|
Griffin et al. (2014) found that the D500N variant did not impair GARS function in 2 in vitro assays: the variant had normal enzyme activity and showed normal intracellular localization. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2D</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GARS1, PRO244LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852648,
|
|
|
|
|
|
|
|
ClinVar: RCV000009789
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese patient with Charcot-Marie-Tooth disease type 2D (CMT2D; 601472), Abe and Hayasaka (2009) identified a heterozygous c.893C-T transition in the GARS gene, resulting in a pro244-to-leu (P244L) substitution in the catalytic domain. The mutation was not identified in 100 controls, is conserved among species, and was predicted to alter the secondary structure of the polypeptide. The patient had onset of the disorder in adolescence and early upper-limb involvement. No mutations in the GARS gene were found in 109 additional Japanese patients with axonal CMT, suggesting that GARS mutations are a rare cause of the disorder in this population. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 SPINAL MUSCULAR ATROPHY, INFANTILE, JAMES TYPE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GARS1, GLY598ALA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs747080824,
|
|
|
|
|
|
gnomAD: rs747080824,
|
|
|
|
|
|
ClinVar: RCV000789772, RCV001260978, RCV003447257
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 7-year-old girl, born of unrelated parents (family 1), with the James type of infantile spinal muscular atrophy (SMAJI; 619042), James et al. (2006) identified a de novo heterozygous c.2313G-C transversion in the GARS1 gene, resulting in a gly598-to-ala (G598A) substitution in the center of the anticodon binding domain. Functional studies of the variant were not performed, but the authors postulated a dominant-negative effect. The patient presented at 6 months of age with lower extremity weakness and did not achieve independent ambulation. </p><p>In a pair of monozygotic twin girls with SMAJI, Eskuri et al. (2012) identified a de novo heterozygous c.1955G-C transversion in the GARS1 gene, resulting in a gly652-to-ala (G652A) substitution, which the authors stated was the same mutation as that reported by James et al. (2006). Functional studies of the variant were not performed, but the patients had a similar phenotype as the girl reported by James et al. (2006). The findings suggested that mutations in the anticodon binding domain may result in a severe phenotype with infantile onset. </p><p><strong><em>Variant Function</em></strong></p><p>
|
|
Using in vitro studies, Griffin et al. (2014) demonstrated that the G598A mutation had less than 10% aminoacylation activity compared to wildtype. The G598A mutant protein did not associate normally with puncta in a neuroblastoma cell line, suggesting that reduced localization to axons may be a component of the pathogenesis. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GARS1, HIS216ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs768987322,
|
|
|
|
|
|
gnomAD: rs768987322,
|
|
|
|
|
|
ClinVar: RCV000857176, RCV001253591, RCV001260979, RCV003482320, RCV004768719, RCV005092541
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient (patient 1) and his mother with autosomal dominant distal hereditary motor neuronopathy-5 (HMND5; 600794), Boczonadi et al. (2018) identified a heterozygous c.647A-G transition in the GARS1 gene, resulting in a his216-to-arg (H216R) substitution. The mutation was identified through sequencing of a gene panel. Patient fibroblasts did not show a defect in mitochondrial translation, but detailed studies on induced neuronal progenitor cells derived from patient fibroblasts showed decreased levels of mitochondrial respiratory chain complexes, impaired mitochondrial respiration and metabolism, defects in calcium flux dynamics, and increased autophagic vacuoles. These findings were consistent with tissue-specific effects of the mutation; the authors postulated a dominant gain-of-function mechanism. The patients had onset of upper limb-predominant distal neuropathy in their early twenties. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 SPINAL MUSCULAR ATROPHY, INFANTILE, JAMES TYPE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GARS1, GLU125LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs797044855,
|
|
|
|
|
|
|
|
ClinVar: RCV000190657, RCV001260977
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 14-month-old infant (patient 2) with the James type of infantile spinal muscular atrophy (SMAJI; 619042), Forrester et al. (2020) identified a heterozygous c.373G-A transition (c.373G-A, NM_002047.2) in the GARS1 gene, resulting in a glu125-to-lys (E125K) substitution. The mutation was found by next-generation sequencing and confirmed by Sanger sequencing; functional studies and studies of patient cells were not performed. There was no mention of family history, segregation of the mutation, or genetic testing of the parents. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 SPINAL MUSCULAR ATROPHY, INFANTILE, JAMES TYPE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GARS1, ILE334ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1554338262,
|
|
|
|
|
|
|
|
ClinVar: RCV000653928, RCV001260980, RCV001334991
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated children (patients 1 and 2), both of Hispanic descent, with the James type of infantile spinal muscular atrophy (SMAJI; 619042), Markovitz et al. (2020) identified a de novo heterozygous c.1001T-A transversion (c.1001T-A, NM_002047.2) in the GARS1 gene, resulting in an ile334-to-asn (I334N) substitution at a highly conserved residue in the catalytic domain. The mutation, which found by trio-based exome sequencing, was not present in the gnomAD database. In vitro functional complementation studies showed that the I334N variant was unable to rescue the growth defect phenotype in yeast with deletion of this ortholog, consistent with a loss-of-function effect. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 SPINAL MUSCULAR ATROPHY, INFANTILE, JAMES TYPE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GARS1, GLY652ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1783251037,
|
|
|
|
|
|
|
|
ClinVar: RCV001260981
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 14-month-old infant (patient 3) with the James type of infantile spinal muscular atrophy (SMAJI; 619042), Markovitz et al. (2020) identified a de novo heterozygous c.1954G-C transversion (c.1954G-C, NM_002047.2) in the GARS1 gene, resulting in a gly652-to-arg (G652R) substitution at a highly conserved residue in the anticodon binding domain. The mutation, which found by trio-based exome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. The affected residue was the same as that identified in other patients with a similar phenotype (600287.0007). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2D</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GARS1, SER265TYR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1554337974,
|
|
|
|
|
|
|
|
ClinVar: RCV001265531
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 Malian sibs, aged 19 and 35 years, with axonal Charcot-Marie-Tooth disease type 2D (CMT2D; 601472), who were born to consanguineous parents of Bambara ethnicity, Yalcouye et al. (2019) identified a c.794C-A transversion in the GARS1 gene, resulting in a ser265-to-tyr (S265Y) substitution in a conserved region of the protein. The patients' mother also had the mutation but was asymptomatic, suggesting incomplete penetrance. The mutation was identified by next-generation sequencing of a panel of 50 genes associated with CMT. The variant was not found in the ExAC, dbSNP, or 1000 Genomes Project databases. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
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<strong>.0013 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 5</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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GARS1, HIS472ARG
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<br />
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SNP: rs1060502838,
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ClinVar: RCV000459084, RCV000664213, RCV000789777, RCV000790256, RCV003332179, RCV004022757
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</span>
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<span class="mim-text-font">
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<p>In 3 affected members of a large multigenerational family with autosomal dominant distal hereditary motor neuronopathy-5 (HMND5; 600794), Forrester et al. (2020) identified a heterozygous c.1415A-G transition (c.1415A-G, NM_002047.2) in the GARS1 gene, resulting in a his472-to-arg (H472R) substitution. An unrelated patient (patient 6) with the disorder also carried the mutation. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Functional studies of the variant and studies of patient cells were not performed, but it was classified as pathogenic by ACMG criteria. Forrester et al. (2020) noted that Griffin et al. (2014) found that the H472R variant reduced aminoacyl-tRNA synthetase activity to 6.25% compared to wildtype. </p>
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</span>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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 class="row">
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Hilary J. Vernon - updated : 07/21/2022<br>Bao Lige - updated : 04/04/2022<br>Cassandra L. Kniffin - updated : 12/01/2020<br>Hilary J. Vernon - updated : 11/16/2020<br>Cassandra L. Kniffin - updated : 10/08/2020<br>Patricia A. Hartz - updated : 07/19/2016<br>Patricia A. Hartz - updated : 07/19/2016<br>Patricia A. Hartz - updated : 07/19/2016<br>Cassandra L. Kniffin - updated : 2/23/2015<br>Cassandra L. Kniffin - updated : 11/30/2009<br>Cassandra L. Kniffin - updated : 6/23/2009<br>Cassandra L. Kniffin - updated : 9/18/2007<br>Cassandra L. Kniffin - updated : 6/12/2007<br>Cassandra L. Kniffin - updated : 4/17/2003<br>Alan F. Scott - updated : 2/12/1996<br>Alan F. Scott - updated : 9/20/1995
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Victor A. McKusick : 1/6/1995
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carol : 10/19/2023<br>carol : 10/19/2023<br>alopez : 10/18/2023<br>alopez : 10/16/2023<br>carol : 07/21/2022<br>mgross : 04/04/2022<br>alopez : 12/17/2020<br>ckniffin : 12/01/2020<br>carol : 11/16/2020<br>alopez : 10/15/2020<br>ckniffin : 10/08/2020<br>carol : 08/20/2019<br>joanna : 07/20/2016<br>alopez : 07/19/2016<br>alopez : 07/19/2016<br>alopez : 07/19/2016<br>alopez : 03/18/2016<br>carol : 2/25/2015<br>mcolton : 2/25/2015<br>ckniffin : 2/23/2015<br>terry : 9/7/2012<br>carol : 8/1/2012<br>carol : 11/22/2011<br>wwang : 12/16/2009<br>wwang : 12/16/2009<br>ckniffin : 11/30/2009<br>wwang : 6/26/2009<br>ckniffin : 6/23/2009<br>wwang : 9/25/2007<br>ckniffin : 9/18/2007<br>wwang : 6/28/2007<br>ckniffin : 6/12/2007<br>ckniffin : 3/16/2007<br>alopez : 4/30/2003<br>carol : 4/18/2003<br>ckniffin : 4/17/2003<br>terry : 4/17/1996<br>mark : 2/12/1996<br>mimadm : 9/23/1995<br>carol : 1/6/1995
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