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- *604544 - LEUCYL-tRNA SYNTHETASE 2; LARS2
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- OMIM
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<p>
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<span class="h4">*604544</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<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/604544">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000011376;t=ENST00000645846" 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=23395" 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=604544" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000011376;t=ENST00000645846" 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_001368263,NM_015340,XM_011533554,XM_017006042,XM_047447829,XM_047447830" 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_015340" 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=604544" 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=05178&isoform_id=05178_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/LARS2" 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/2501029,7661872,13548630,19683964,119585144,767922828,929653729,1034632206,1565200264,2217342941,2217342944,2462588513,2462588515,2462588517,2462588519" 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/Q15031" 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=23395" 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=ENSG00000011376;t=ENST00000645846" 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=LARS2" 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=LARS2" 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+23395" 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/LARS2" 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:23395" 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/23395" 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=chr3&hgg_gene=ENST00000645846.2&hgg_start=45388576&hgg_end=45549407&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:17095" 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/lars2" 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=604544[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=604544[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/ENSG00000011376" 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=LARS2" 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=LARS2" 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=LARS2" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=LARS2&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/PA134982982" 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:17095" 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/FBgn0027085.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:2142973" 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/LARS2#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:2142973" 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/23395/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=23395" 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=WBGene00003074;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-070928-3" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:23395" 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=LARS2&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> 1237349008<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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604544
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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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LEUCYL-tRNA SYNTHETASE 2; LARS2
|
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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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
LEUCYL-tRNA SYNTHETASE, MITOCHONDRIAL<br />
|
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MITOCHONDRIAL LEURS
|
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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>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=LARS2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">LARS2</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>
|
|
<span class="mim-text-font">
|
|
<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/3/238?start=-3&limit=10&highlight=238">3p21.31</a>
|
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:45388576-45549407&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'})">3:45,388,576-45,549,407</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>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=617021,615300" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/3/238?start=-3&limit=10&highlight=238">
|
|
3p21.31
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Hydrops, lactic acidosis, and sideroblastic anemia
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/617021"> 617021 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
|
</span>
|
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</td>
|
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|
|
</tr>
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|
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|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Perrault syndrome 4
|
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|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/615300"> 615300 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
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</tbody>
|
|
</table>
|
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</div>
|
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</div>
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<div>
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<p>The LARS2 gene encodes mitochondrial leucyl-tRNA synthetase (summary by <a href="#9" class="mim-tip-reference" title="Solda, G., Caccia, S., Robusto, M., Chiereghin, C., Castorina, P., Ambrosetti, U., Duga, S., Asselta, R. <strong>First independent replication of the involvement of LARS2 in Perrault syndrome by whole-exome sequencing of an Italian family.</strong> J. Hum. Genet. 61: 295-300, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26657938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26657938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26657938[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/jhg.2015.149" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26657938">Solda et al., 2016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26657938" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By searching databases for aminoacyl-tRNA synthetases containing a mitochondrial targeting sequence, <a href="#1" class="mim-tip-reference" title="Bonnefond, L., Fender, A., Rudinger-Thirion, J., Giege, R., Florentz, C., Sissler, M. <strong>Toward the full set of human mitochondrial aminoacyl-tRNA synthetases: characterization of AspRS and TyrRS.</strong> Biochemistry 44: 4805-4816, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15779907/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15779907</a>] [<a href="https://doi.org/10.1021/bi047527z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15779907">Bonnefond et al. (2005)</a> identified LARS2, which they called mitochondrial LEURS. The deduced 903-amino acid protein has an N-terminal mitochondrial targeting signal that is cleaved after residue 39. LARS2 has characteristics of a class I aminoacyl-tRNA synthetase, including a classical Rossmann fold. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15779907" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using Northern blot analysis, <a href="#5" class="mim-tip-reference" title="Li, R., Guan, M.-X. <strong>Human mitochondrial leucyl-tRNA synthetase corrects mitochondrial dysfunctions due to the tRNA(Leu(UUR)) A3243G mutation, associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms and diabetes.</strong> Molec. Cell. Biol. 30: 2147-2154, 2010. Note: Erratum: Molec. Cell. Biol. 37: e00335-17, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20194621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20194621</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20194621[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/10.1128/MCB.01614-09" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20194621">Li and Guan (2010)</a> detected ubiquitous but variable LARS2 expression, with highest expression in tissues with high metabolic rates, such as skeletal muscle, heart, and kidney. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20194621" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#1" class="mim-tip-reference" title="Bonnefond, L., Fender, A., Rudinger-Thirion, J., Giege, R., Florentz, C., Sissler, M. <strong>Toward the full set of human mitochondrial aminoacyl-tRNA synthetases: characterization of AspRS and TyrRS.</strong> Biochemistry 44: 4805-4816, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15779907/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15779907</a>] [<a href="https://doi.org/10.1021/bi047527z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15779907">Bonnefond et al. (2005)</a> determined that the LARS2 gene contains 20 exons and spans 153 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15779907" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#10" class="mim-tip-reference" title="Szeles, A., Yang, Y., Sandlund, A. M., Kholodnyuck, I., Kiss, H., Kost-Alimova, M., Zabarovsky, E. R., Stanbridge, E., Klein, G., Imreh, S. <strong>Human/mouse microcell hybrid based on elimination test reduces the putative tumor suppressor region at 3p21.3 to 1.6 cM.</strong> Genes Chromosomes Cancer 20: 329-336, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9408748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9408748</a>]" pmid="9408748">Szeles et al. (1997)</a> used an experimental system, the elimination test, to identify a 1-Mb segment commonly lost in chromosomal deletions on 3p in a large number of human tumors. The region was referred to as the chromosome 3 common eliminated region-1, or C3CER1. Using the sequence of 2 overlapping PACs from C3CER1, <a href="#2" class="mim-tip-reference" title="Kiss, H., Kedra, D., Yang, Y., Kost-Alimova, M., Kiss, C., O'Brien, K. P., Fransson, I., Klein, G., Imreh, S., Dumanski, J. P. <strong>A novel gene containing LIM domains (LIMD1) is located within the common eliminated region 1 (C3CER1) in 3p21.3.</strong> Hum. Genet. 105: 552-559, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10647888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10647888</a>] [<a href="https://doi.org/10.1007/s004399900188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10647888">Kiss et al. (1999)</a> localized the cDNA encoding the precursor of mitochondrial leucyl-tRNA synthetase to the 3p21.3 region. They localized a second gene, LIMD1 (<a href="/entry/604543">604543</a>), very close to the LARS2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9408748+10647888" 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>The 3243A-G mutation (<a href="/entry/590050#0001">590050.0001</a>) in tRNA-leu(UUR) (MTTL1; <a href="/entry/590050">590050</a>), where R = A or G, causes MELAS syndrome (<a href="/entry/540000">540000</a>). The primary defect with this mutation is inefficient aminoacylation of mutant tRNA-leu(UUR), causing mitochondrial dysfunction with reduced rate of RNA processing and protein synthesis and defects in respiration. From human cytoplasmic hybrids (cybrids) containing 3243A-G mutant or wildtype mitochondria from heteroplasmic MELAS patient myoblasts, <a href="#5" class="mim-tip-reference" title="Li, R., Guan, M.-X. <strong>Human mitochondrial leucyl-tRNA synthetase corrects mitochondrial dysfunctions due to the tRNA(Leu(UUR)) A3243G mutation, associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms and diabetes.</strong> Molec. Cell. Biol. 30: 2147-2154, 2010. Note: Erratum: Molec. Cell. Biol. 37: e00335-17, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20194621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20194621</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20194621[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/10.1128/MCB.01614-09" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20194621">Li and Guan (2010)</a> developed a nearly homoplastic mutant cybrid line and an isogenic homoplastic wildtype cybrid line. They found that overexpression of LARS2 in the mutant cybrid line, but not the wildtype cybrid line, increased the steady-state level of aminoacylated tRNA-leu(UUR) and the rate of RNA processing and translation and restored mitochondrial respiration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20194621" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Perrault Syndrome 4</em></strong></p><p>
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In affected individuals with Perrault syndrome-4 (PRLTS4; <a href="/entry/615300">615300</a>) from a consanguineous family of Palestinian ancestry and a family of Slovenian ancestry, <a href="#6" class="mim-tip-reference" title="Pierce, S. B., Gersak, K., Michaelson-Cohen, R., Walsh, T., Lee, M. K., Malach, D., Klevit, R. E., King, M.-C., Levy-Lahad, E. <strong>Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome.</strong> Am. J. Hum. Genet. 92: 614-620, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23541342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23541342</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23541342[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.03.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23541342">Pierce et al. (2013)</a> identified homozygous and compound heterozygous mutations in the LARS2 gene (<a href="#0001">604544.0001</a>-<a href="#0003">604544.0003</a>, respectively). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23541342" 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 sister and brother, born of unrelated Italian parents, with PRLTS4, <a href="#9" class="mim-tip-reference" title="Solda, G., Caccia, S., Robusto, M., Chiereghin, C., Castorina, P., Ambrosetti, U., Duga, S., Asselta, R. <strong>First independent replication of the involvement of LARS2 in Perrault syndrome by whole-exome sequencing of an Italian family.</strong> J. Hum. Genet. 61: 295-300, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26657938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26657938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26657938[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/jhg.2015.149" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26657938">Solda et al. (2016)</a> identified compound heterozygous missense mutations in the LARS2 gene (T300M, <a href="#0004">604544.0004</a> and E638K, <a href="/entry/603544#0005">603544.0005</a>). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro 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=26657938" 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 Japanese sisters with PRLTS4, <a href="#3" class="mim-tip-reference" title="Kosaki, R., Horikawa, R., Fujii, E., Kosaki, K. <strong>Biallelic mutations in LARS2 can cause Perrault syndrome type 2 with neurologic symptoms.</strong> Am. J. Med. Genet. 176A: 404-408, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29205794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29205794</a>] [<a href="https://doi.org/10.1002/ajmg.a.38552" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29205794">Kosaki et al. (2018)</a> identified compound heterozygous missense mutations in the LARS2 gene (E294K, <a href="/entry/604655#0007">604655.0007</a> and T519M, <a href="#0008">604544.0008</a>). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither variant was found among 2,049 Japanese controls, but both were found at very low frequencies in the ExAC database. Functional studies of the variants were not performed, but they were considered likely pathogenic according to ACMG criteria. The patients also had neurodevelopmental abnormalities with learning difficulties and behavioral abnormalities, thus expanding the phenotypic spectrum of PRLTS4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29205794" 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 4 unrelated patients, 2 females and 2 males, with PRLTS4, <a href="#11" class="mim-tip-reference" title="van der Knaap, M. S., Bugiani, M., Mendes, M. I., Riley, L. G., Smith, D. E. C., Rudinger-Thirion, J., Frugier, M., Breur, M., Crawford, J., van Gaalen, J., Schouten, M., Willems, M., and 10 others. <strong>Biallelic variants in LARS2 and KARS cause deafness and (ovario)leukodystrophy.</strong> Neurology 92: e1225-e1237, 2019. Note: Electronic Article. Erratum: Neurology 93: 982 only, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30737337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30737337</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30737337[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/10.1212/WNL.0000000000007098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30737337">van der Knaap et al. (2019)</a> identified compound heterozygous mutations in the LARS2 gene (see, e.g., <a href="#0007">604544.0007</a>; <a href="#0009">604544.0009</a>-<a href="#0011">604544.0011</a>). The mutations, which were found by whole-genome or whole-exome sequencing, segregated with the disorder in all patients from whom parental DNA was available. Patient-derived mitochondria showed decreased LARS2 aminoacylation activity (about 50% of controls). In addition to deafness and ovarian failure (in the females), the patients had neurologic involvement, both behavioral and motor, as well as leukodystrophy on brain imaging. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30737337" 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>Hydrops, Lactic Acidosis, and Sideroblastic Anemia</em></strong></p><p>
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In a female infant, born of unrelated Pakistani parents, with hydrops, lactic acidosis, and sideroblastic anemia (HLASA; <a href="/entry/617021">617021</a>) resulting in death at age 5 days, <a href="#8" class="mim-tip-reference" title="Riley, L. G., Rudinger-Thirion, J., Schmitz-Abe, K., Thorburn, D. R., Davis, R. L., Teo, J., Arbuckle, S., Cooper, S. T., Campagna, D. R., Frugier, M., Markianos, K., Sue, C. M., Fleming, M. D., Christodoulou, J. <strong>LARS2 variants associated with hydrops, lactic acidosis, sideroblastic anemia, and multisystem failure.</strong> JIMD Rep. 28: 49-57, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26537577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26537577</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26537577[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/10.1007/8904_2015_515" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26537577">Riley et al. (2016)</a> identified compound heterozygous missense mutations in the LARS2 gene (T522N, <a href="#0001">604544.0001</a> and A430V, <a href="#0006">604544.0006</a>). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies in E. coli showed that the variants resulted in variable decreases in catalytic activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26537577" 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 boys from 2 unrelated families (families 1 and 2) with HLASA, <a href="#7" class="mim-tip-reference" title="Riley, L. G., Rudinger-Thirion, J., Frugier, M., Wilson, M., Luig, M., Alahakoon, T. I., Nixon, C. Y., Kirk, E. P., Roscioli, T., Lunke, S., Stark, Z., Wierenga, K. J., Palle, S., Walsh, M., Higgs, E., Arbuckle, S., Thirukeswaran, S., Compton, A. G., Thorburn, D. R., Christodoulou, J. <strong>The expanding LARS2 phenotypic spectrum: HLASA, Perrault syndrome with leukodystrophy, and mitochondrial myopathy.</strong> Hum. Mutat. 41: 1425-1434, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32442335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32442335</a>] [<a href="https://doi.org/10.1002/humu.24050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32442335">Riley et al. (2020)</a> identified compound heterozygous missense mutations in the LARS2 gene (<a href="#0011">604544.0011</a>-<a href="#0014">604544.0014</a>). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. None was present in the gnomAD database. In vitro functional expression studies of these recombinant variants showed that all resulted in decreased LARS2 aminoacylation activity compared to controls, although some had more severe effects on enzyme activity than others. The authors postulated that the degree of impaired enzyme activity correlated with the severity of the phenotype, such that HLASA-associated LARS2 mutations have a more detrimental effect compared to PRLTS4-associated mutations. However, there is a phenotypic spectrum with overlapping clinical features between the 2 disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32442335" 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="#7" class="mim-tip-reference" title="Riley, L. G., Rudinger-Thirion, J., Frugier, M., Wilson, M., Luig, M., Alahakoon, T. I., Nixon, C. Y., Kirk, E. P., Roscioli, T., Lunke, S., Stark, Z., Wierenga, K. J., Palle, S., Walsh, M., Higgs, E., Arbuckle, S., Thirukeswaran, S., Compton, A. G., Thorburn, D. R., Christodoulou, J. <strong>The expanding LARS2 phenotypic spectrum: HLASA, Perrault syndrome with leukodystrophy, and mitochondrial myopathy.</strong> Hum. Mutat. 41: 1425-1434, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32442335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32442335</a>] [<a href="https://doi.org/10.1002/humu.24050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32442335">Riley et al. (2020)</a> reported a 17-year-old boy with a reversible mitochondrial myopathy associated with compound heterozygous missense variants in the LARS2 gene (R103H and D518N). The variants, which were found by exome sequencing and confirmed by Sanger sequencing, were each inherited from an unaffected parent. Both were found in the gnomAD database: R103H had a frequency of 1.6 x 10(-5), whereas R518N had a frequency of 0.0039; there were 6 homozygous carriers of R518N in gnomAD. The patient presented in infancy with mildly delayed motor development and pronounced neck muscle weakness. Later in childhood, he had hypotonia, limb muscle weakness, positive Gowers sign, and awkward running. By adolescence, structured exercise programs improved his stamina and he was able to participate in sports. At age 17 years, he had normal muscle bulk and strength with negative Gowers sign. Cognitive function, hearing, and vision were normal. Laboratory studies were notable for increased blood lactate and creatine kinase. Muscle biopsy showed variation in fiber size with a reduction in type 1 fibers, mildly increased central nuclei, and abnormal subsarcolemmal accumulation of enlarged pleiomorphic mitochondria, consistent with a mitochondrial myopathy. Analysis of muscle mitochondrial respiratory chain complexes showed isolated low complex I activity compared to controls. LARS2 protein levels were decreased in patient muscle (20% of controls), but normal in fibroblasts. In vitro studies showed that LARS2 aminoacylation catalytic efficiency was reduced for each mutant (a 2-fold loss for R103H and a 6-fold loss for D518N); enzymatic activity for R103H was particularly low when ATP concentrations were decreased. The authors noted the unusual phenotype associated with LARS2 variants. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32442335" 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>To identify in a systematic manner all of the gene classes that control C. elegans life span, <a href="#4" class="mim-tip-reference" title="Lee, S. S., Lee, R. Y. N., Fraser, A. G., Kamath, R. S., Ahringer, J., Ruvkun, G. <strong>A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity.</strong> Nature Genet. 33: 40-48, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12447374/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12447374</a>] [<a href="https://doi.org/10.1038/ng1056" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12447374">Lee et al. (2003)</a> used a set of more than 5,600 genes in an RNA interference (RNAi) screen to identify genes that extend life span when inactivated. The screen showed that a large number of genes essential for mitochondrial function have critical roles in determining C. elegans life span. Consistent with these results, in a classic genetic screen for increased life span, they found that a probable null mutation in a mitochondrial leucyl-tRNA synthetase gene, Lrs2, resulted in a markedly longer life span. Long-lived worms with impaired mitochondria had lower ATP content and oxygen consumption, but differential responses to free-radical and other stresses. These data suggested that the longer life span cannot simply be assigned to lower free radical production and suggested a more complex coupling of metabolism and longevity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12447374" 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="Pierce, S. B., Gersak, K., Michaelson-Cohen, R., Walsh, T., Lee, M. K., Malach, D., Klevit, R. E., King, M.-C., Levy-Lahad, E. <strong>Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome.</strong> Am. J. Hum. Genet. 92: 614-620, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23541342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23541342</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23541342[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.03.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23541342">Pierce et al. (2013)</a> confirmed that a C. elegans strain homozygous for a null mutation (T247X) in LARS2 are completely sterile and produce no progeny at all, in contrast to wildtype worms that produce 200 to 250 progeny per animal. Germ cell development was arrested, such that oocytes were never observed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23541342" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=604544[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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In a sister and 2 brothers with Perrault syndrome (PRLTS4; <a href="/entry/615300">615300</a>) from a consanguineous family of Palestinian ancestry, <a href="#6" class="mim-tip-reference" title="Pierce, S. B., Gersak, K., Michaelson-Cohen, R., Walsh, T., Lee, M. K., Malach, D., Klevit, R. E., King, M.-C., Levy-Lahad, E. <strong>Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome.</strong> Am. J. Hum. Genet. 92: 614-620, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23541342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23541342</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23541342[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.03.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23541342">Pierce et al. (2013)</a> identified homozygosity for a c.1565C-A transversion at chr3:45,537,808C-A (GRCh37) in the LARS2 gene, resulting in a thr522-to-asn (T522N) substitution at a highly conserved residue in the catalytic domain, located at the N-terminal end of an alpha-helix that forms part of a pocket into which the 3-prime end of the tRNA strand binds. The mutation was present in heterozygosity in their unaffected parents, but was not found in 239 Palestinian or 362 Slovenian controls, or in 6,500 controls of European American or African American ancestry in the NHLBI Exome Variant Server. Functional analysis in a yeast complementation assay showed only partial rescue of red pigment production with the T522N variant, indicating reduced activity relative to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23541342" 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>Hydrops, Lactic Acidosis, and Sideroblastic Anemia</em></strong></p><p>
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In a female infant, born of unrelated Pakistani parents, with hydrops, lactic acidosis, and sideroblastic anemia (HLASA; <a href="/entry/617021">617021</a>) resulting in death at age 5 days, <a href="#8" class="mim-tip-reference" title="Riley, L. G., Rudinger-Thirion, J., Schmitz-Abe, K., Thorburn, D. R., Davis, R. L., Teo, J., Arbuckle, S., Cooper, S. T., Campagna, D. R., Frugier, M., Markianos, K., Sue, C. M., Fleming, M. D., Christodoulou, J. <strong>LARS2 variants associated with hydrops, lactic acidosis, sideroblastic anemia, and multisystem failure.</strong> JIMD Rep. 28: 49-57, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26537577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26537577</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26537577[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/10.1007/8904_2015_515" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26537577">Riley et al. (2016)</a> identified compound heterozygous missense mutations in the LARS2 gene: a T522N substitution in the catalytic domain, and a c.1289C-T transition, resulting in an ala430-to-val (A430V) substitution (<a href="#0006">604544.0006</a>) at a partially conserved residue in the CP1 editing domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and were not found in the Exome Variant Server database or in 345 controls exomes. A430V was not found in the ExAC database, whereas T522N was found at a low frequency (0.0002). In vitro functional expression studies in E. coli showed that the A430V variant resulted in an 18-fold loss of catalytic activity, whereas the T522N variant resulted in a 9-fold reduction compared to wildtype. Immunoblot analysis showed normal levels of LARS2 in patient muscle, but about a 50% decrease in patient liver. Levels of mitochondrial complex proteins, particularly complex I, were decreased in patient liver and less so in patient muscle, but not in patient fibroblasts. There was no defect in mitochondrial protein synthesis in patient fibroblasts or induced myotubes, suggesting that the variants only affect tissue with higher energy demands. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26537577" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs398123036 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398123036;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/rs398123036?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=rs398123036" 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=rs398123036" 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=RCV000049286 OR RCV001544530 OR RCV002513678" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000049286, RCV001544530, RCV002513678" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000049286...</a>
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<p>In a woman of Slovenian ancestry with premature ovarian failure and severe hearing loss (PRLTS4; <a href="/entry/615300">615300</a>), <a href="#6" class="mim-tip-reference" title="Pierce, S. B., Gersak, K., Michaelson-Cohen, R., Walsh, T., Lee, M. K., Malach, D., Klevit, R. E., King, M.-C., Levy-Lahad, E. <strong>Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome.</strong> Am. J. Hum. Genet. 92: 614-620, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23541342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23541342</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23541342[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.03.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23541342">Pierce et al. (2013)</a> identified compound heterozygosity for 2 mutations in the LARS2 gene: a c.1866C-T transition at chr3:45,557,610 (GRCh37), resulting in a thr629-to-met (T629M) substitution at a residue conserved in mammals, and a 1-bp deletion (c.1077delT; <a href="#0003">604544.0003</a>) at chr3:45,527,241 (GRCh37), predicted to yield a 373-amino acid truncated protein with 14 novel amino acids at the C terminus (Ile360PhefsTer15). Her unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in 239 Palestinian or 362 Slovenian controls, or in 6,500 controls of European American or African American ancestry in the NHLBI Exome Variant Server. Functional analysis in a yeast complementation assay showed no rescue of red pigment production with the 1077delT variant, indicating that it represents a nonfunctional variant; in contrast, the T629M variant produced enough activity to support wildtype production of red pigment. <a href="#6" class="mim-tip-reference" title="Pierce, S. B., Gersak, K., Michaelson-Cohen, R., Walsh, T., Lee, M. K., Malach, D., Klevit, R. E., King, M.-C., Levy-Lahad, E. <strong>Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome.</strong> Am. J. Hum. Genet. 92: 614-620, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23541342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23541342</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23541342[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.03.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23541342">Pierce et al. (2013)</a> suggested that the compound heterozygous combination of LARS2 T629M and 1077delT yields reduced total LARS2 activity, resulting in inadequate mitochondrial function in the ovary and inner ear. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23541342" 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">rs398123037 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398123037;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=rs398123037" 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=rs398123037" 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=RCV000049287 OR RCV002513679" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000049287, RCV002513679" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000049287...</a>
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<p>For discussion of the 1-bp deletion in the LARS2 gene (c.1077delT) that was found in compound heterozygous state in a woman with premature ovarian failure and severe hearing loss (PRLTS4; <a href="/entry/615300">615300</a>) by <a href="#6" class="mim-tip-reference" title="Pierce, S. B., Gersak, K., Michaelson-Cohen, R., Walsh, T., Lee, M. K., Malach, D., Klevit, R. E., King, M.-C., Levy-Lahad, E. <strong>Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome.</strong> Am. J. Hum. Genet. 92: 614-620, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23541342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23541342</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23541342[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.03.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23541342">Pierce et al. (2013)</a>, see <a href="#0002">604544.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23541342" 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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LARS2, THR300MET
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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> rs864309642 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864309642;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/rs864309642?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=rs864309642" 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=rs864309642" 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=RCV000203256 OR RCV000203257 OR RCV003556221" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000203256, RCV000203257, RCV003556221" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000203256...</a>
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<p>In a brother and sister, born of unrelated Italian parents, with Perrault syndrome-4 (PRLTS4; <a href="/entry/615300">615300</a>), <a href="#9" class="mim-tip-reference" title="Solda, G., Caccia, S., Robusto, M., Chiereghin, C., Castorina, P., Ambrosetti, U., Duga, S., Asselta, R. <strong>First independent replication of the involvement of LARS2 in Perrault syndrome by whole-exome sequencing of an Italian family.</strong> J. Hum. Genet. 61: 295-300, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26657938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26657938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26657938[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/jhg.2015.149" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26657938">Solda et al. (2016)</a> identified compound heterozygous missense mutations in the LARS2 gene: a c.899C-T transition (c.899C-T, NM_015340.3), resulting in a thr300-to-met (T300M) substitution in the editing domain, and a c.1912G-A transition, resulting in a glu638-to-lys (E638K; <a href="/entry/604655#0005">604655.0005</a>) substitution in the catalytic domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were filtered against the dbSNP (build 135), 1000 Genomes Project, and Exome Sequencing Project databases, and segregated with the disorder in the family. The mutations were not found in the ExAC database or in an in-house database of 3,500 ethnically matched controls. The E638 residue is highly conserved, whereas the T300 residue is conserved in mammals, but not in more distantly related species. Molecular modeling based on the E. coli structure suggested that both mutations would be deleterious. In vitro functional studies and studies on patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26657938" 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">rs864309643 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864309643;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=rs864309643" 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=rs864309643" 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=RCV000203255" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000203255" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000203255</a>
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<p>For discussion of the c.1912G-A transition (c.1912G-A, NM_015340.3) in the LARS2 gene, resulting in a glu638-to-lys (E638K) substitution, that was found in compound heterozygous state in 2 sibs with Perrault syndrome-4 (PRLTS4; <a href="/entry/615300">615300</a>) by <a href="#9" class="mim-tip-reference" title="Solda, G., Caccia, S., Robusto, M., Chiereghin, C., Castorina, P., Ambrosetti, U., Duga, S., Asselta, R. <strong>First independent replication of the involvement of LARS2 in Perrault syndrome by whole-exome sequencing of an Italian family.</strong> J. Hum. Genet. 61: 295-300, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26657938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26657938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26657938[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/jhg.2015.149" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26657938">Solda et al. (2016)</a>, see <a href="/entry/604655#0004">604655.0004</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26657938" 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 HYDROPS, LACTIC ACIDOSIS, AND SIDEROBLASTIC ANEMIA (1 patient)</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">rs879255606 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879255606;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=rs879255606" 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=rs879255606" 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=RCV000235638" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000235638" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000235638</a>
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<p>For discussion of the c.1289C-T transition (c.1289C-T, NM_015349.3) in the LARS2 gene, resulting in an ala430-to-val (A430V) substitution, that was found in compound heterozygous state in a patient with hydrops, lactic acidosis, and sideroblastic anemia (HLASA; <a href="/entry/617021">617021</a>) by <a href="#8" class="mim-tip-reference" title="Riley, L. G., Rudinger-Thirion, J., Schmitz-Abe, K., Thorburn, D. R., Davis, R. L., Teo, J., Arbuckle, S., Cooper, S. T., Campagna, D. R., Frugier, M., Markianos, K., Sue, C. M., Fleming, M. D., Christodoulou, J. <strong>LARS2 variants associated with hydrops, lactic acidosis, sideroblastic anemia, and multisystem failure.</strong> JIMD Rep. 28: 49-57, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26537577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26537577</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26537577[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/10.1007/8904_2015_515" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26537577">Riley et al. (2016)</a>, see <a href="#0001">604544.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26537577" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs749627411 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs749627411;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/rs749627411?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=rs749627411" 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=rs749627411" 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=RCV001283750 OR RCV001587314 OR RCV002542964" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001283750, RCV001587314, RCV002542964" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001283750...</a>
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<p>In 2 Japanese sisters with Perrault syndrome-4 (PRLTS4; <a href="/entry/615300">615300</a>), <a href="#3" class="mim-tip-reference" title="Kosaki, R., Horikawa, R., Fujii, E., Kosaki, K. <strong>Biallelic mutations in LARS2 can cause Perrault syndrome type 2 with neurologic symptoms.</strong> Am. J. Med. Genet. 176A: 404-408, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29205794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29205794</a>] [<a href="https://doi.org/10.1002/ajmg.a.38552" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29205794">Kosaki et al. (2018)</a> identified compound heterozygous missense mutations in the LARS2 gene: a c.880G-A transition (c.880G-A, NM_015340) in exon 10, resulting in a glu294-to-lys (E294K) substitution, and a c.1556C-T transition in exon 14, resulting in a thr519-to-met (T519M; <a href="#0008">604544.0008</a>) substitution. Both mutations occurred in the editing domain of the tRNA synthetase. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither variant was found among 2,049 Japanese controls, but both were found at very low frequencies in the ExAC database. Functional studies of the variants were not performed, but they were considered likely pathogenic according to ACMG criteria. The patients also had neurodevelopmental abnormalities with learning difficulties and behavioral abnormalities, thus expanding the phenotypic spectrum of PRLTS4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29205794" 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 48-year-old woman (patient 4) with PRLTS4, <a href="#11" class="mim-tip-reference" title="van der Knaap, M. S., Bugiani, M., Mendes, M. I., Riley, L. G., Smith, D. E. C., Rudinger-Thirion, J., Frugier, M., Breur, M., Crawford, J., van Gaalen, J., Schouten, M., Willems, M., and 10 others. <strong>Biallelic variants in LARS2 and KARS cause deafness and (ovario)leukodystrophy.</strong> Neurology 92: e1225-e1237, 2019. Note: Electronic Article. Erratum: Neurology 93: 982 only, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30737337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30737337</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30737337[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/10.1212/WNL.0000000000007098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30737337">van der Knaap et al. (2019)</a> identified compound heterozygosity for the E294K mutation and R228H (see <a href="#0011">604544.0011</a>). The mutations were found by exome sequencing: E294K was present at a low frequency (0.0016%) in the gnomAD database. Patient-derived mitochondria showed decreased LARS2 aminoacylation activity (about 50% of controls). In addition to deafness and ovarian failure, the patient developed progressive neurologic motor abnormalities as an adult that were associated with leukodystrophy on brain imaging. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30737337" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs141097216 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs141097216;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/rs141097216?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=rs141097216" 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=rs141097216" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the c.1556C-T transition (c.1556C-T, NM_015340) in exon 14 of the LARS2 gene, resulting in a thr519-to-met (T519M) substitution, that was found in compound heterozygous state in 2 sisters with Perrault syndrome-4 (PRLTS4; <a href="/entry/615300">615300</a>) by <a href="#3" class="mim-tip-reference" title="Kosaki, R., Horikawa, R., Fujii, E., Kosaki, K. <strong>Biallelic mutations in LARS2 can cause Perrault syndrome type 2 with neurologic symptoms.</strong> Am. J. Med. Genet. 176A: 404-408, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29205794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29205794</a>] [<a href="https://doi.org/10.1002/ajmg.a.38552" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29205794">Kosaki et al. (2018)</a>, see <a href="#0007">604544.0007</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29205794" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs774649299 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs774649299;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/rs774649299?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=rs774649299" 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=rs774649299" 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=RCV000496181 OR RCV003441896" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000496181, RCV003441896" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000496181...</a>
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<p>In a 37-year-old man (patient 2) with Perrault syndrome-4 (PRLTS4; <a href="/entry/615300">615300</a>), <a href="#11" class="mim-tip-reference" title="van der Knaap, M. S., Bugiani, M., Mendes, M. I., Riley, L. G., Smith, D. E. C., Rudinger-Thirion, J., Frugier, M., Breur, M., Crawford, J., van Gaalen, J., Schouten, M., Willems, M., and 10 others. <strong>Biallelic variants in LARS2 and KARS cause deafness and (ovario)leukodystrophy.</strong> Neurology 92: e1225-e1237, 2019. Note: Electronic Article. Erratum: Neurology 93: 982 only, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30737337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30737337</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30737337[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/10.1212/WNL.0000000000007098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30737337">van der Knaap et al. (2019)</a> identified compound heterozygous missense mutations in the LARS2 gene: a c.1987C-T transition (c.1987C-T, NM_015340.3), resulting in an arg663-to-trp (R663W) substitution between the catalytic and tRNA-binding domains, and a c.371A-T transversion, resulting in an asn124-to-ile (N124I; <a href="#0010">604544.0010</a>) substitution in the catalytic domain. Both mutations occurred at conserved residues. The mutations, which were found by whole-exome sequencing, were each inherited from an unaffected parent. The R663W variant was found at a low frequency (0.0012%) in the gnomAD database, whereas N124I was not present. In vitro functional expression studies of purified recombinant variants showed a 3-fold loss of LARS2 catalytic aminoacylation activity compared to controls. Binding to tRNA was not affected by the mutations. Patient-derived mitochondria also showed decreased LARS2 activity (about 50% of controls) without effects on mitochondrial respiratory chain complexes. In addition to deafness, the patient had progressive neurologic abnormalities, both behavioral and motor, and leukodystrophy on brain imaging. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30737337" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs776171893 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs776171893;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/rs776171893?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=rs776171893" 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=rs776171893" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the c.371A-T transversion (c.371A-T, NM_015340.3) in the LARS2 gene, resulting in an asn124-to-ile (N124I) substitution, that was found in compound heterozygous state in a patient with Perrault syndrome-4 (PRLTS4; <a href="/entry/615300">615300</a>) by <a href="#11" class="mim-tip-reference" title="van der Knaap, M. S., Bugiani, M., Mendes, M. I., Riley, L. G., Smith, D. E. C., Rudinger-Thirion, J., Frugier, M., Breur, M., Crawford, J., van Gaalen, J., Schouten, M., Willems, M., and 10 others. <strong>Biallelic variants in LARS2 and KARS cause deafness and (ovario)leukodystrophy.</strong> Neurology 92: e1225-e1237, 2019. Note: Electronic Article. Erratum: Neurology 93: 982 only, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30737337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30737337</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30737337[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/10.1212/WNL.0000000000007098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30737337">van der Knaap et al. (2019)</a>, see <a href="#0009">604544.0009</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30737337" 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">rs770440975 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs770440975;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=rs770440975" 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=rs770440975" 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=RCV000993581 OR RCV001283752 OR RCV002538373" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000993581, RCV001283752, RCV002538373" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000993581...</a>
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In a 48-year-old woman (patient 4) with Perrault syndrome-4 (PRLTS4; <a href="/entry/615300">615300</a>), <a href="#11" class="mim-tip-reference" title="van der Knaap, M. S., Bugiani, M., Mendes, M. I., Riley, L. G., Smith, D. E. C., Rudinger-Thirion, J., Frugier, M., Breur, M., Crawford, J., van Gaalen, J., Schouten, M., Willems, M., and 10 others. <strong>Biallelic variants in LARS2 and KARS cause deafness and (ovario)leukodystrophy.</strong> Neurology 92: e1225-e1237, 2019. Note: Electronic Article. Erratum: Neurology 93: 982 only, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30737337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30737337</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30737337[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/10.1212/WNL.0000000000007098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30737337">van der Knaap et al. (2019)</a> identified compound heterozygous missense mutations in the LARS2 gene: a c.683G-A transition (c.683G-A, NM_015340.3), resulting in an arg228-to-his (R228H) substitution in the catalytic domain, and E294K (<a href="#0007">604544.0007</a>). The R228H was not present in the gnomAD database. The mutations were found by whole-exome sequencing; the patient's unaffected mother carried the R228H variant, but DNA from the father was not available. Patient-derived mitochondria showed decreased LARS2 aminoacylation activity (about 50% of controls). In addition to deafness and ovarian failure, the patient developed progressive neurologic motor abnormalities as an adult that were associated with leukodystrophy on brain imaging. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30737337" 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>Hydrops, Lactic Acidosis, and Sideroblastic Anemia</em></strong></p><p>
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In an 18-month-old boy (patient 1) with hydrops, lactic acidosis, and sideroblastic anemia (HLASA; <a href="/entry/617021">617021</a>), <a href="#7" class="mim-tip-reference" title="Riley, L. G., Rudinger-Thirion, J., Frugier, M., Wilson, M., Luig, M., Alahakoon, T. I., Nixon, C. Y., Kirk, E. P., Roscioli, T., Lunke, S., Stark, Z., Wierenga, K. J., Palle, S., Walsh, M., Higgs, E., Arbuckle, S., Thirukeswaran, S., Compton, A. G., Thorburn, D. R., Christodoulou, J. <strong>The expanding LARS2 phenotypic spectrum: HLASA, Perrault syndrome with leukodystrophy, and mitochondrial myopathy.</strong> Hum. Mutat. 41: 1425-1434, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32442335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32442335</a>] [<a href="https://doi.org/10.1002/humu.24050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32442335">Riley et al. (2020)</a> identified compound heterozygous missense mutations in the LARS2 gene: R228H and D438G (<a href="#0012">604544.0012</a>). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither was present in the gnomAD database. In vitro functional expression studies of these recombinant variants showed that both resulted in decreased LARS2 aminoacylation activity compared to controls, with R228H having a more severe effect than D438G. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32442335" 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>.0012 HYDROPS, LACTIC ACIDOSIS, AND SIDEROBLASTIC ANEMIA</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">rs1575289366 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1575289366;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=rs1575289366" 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=rs1575289366" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In an 18-month-old boy, born of Japanese and Caucasian parents (family 1), with hydrops, lactic acidosis, and sideroblastic anemia (HLASA; <a href="/entry/617021">617021</a>), <a href="#7" class="mim-tip-reference" title="Riley, L. G., Rudinger-Thirion, J., Frugier, M., Wilson, M., Luig, M., Alahakoon, T. I., Nixon, C. Y., Kirk, E. P., Roscioli, T., Lunke, S., Stark, Z., Wierenga, K. J., Palle, S., Walsh, M., Higgs, E., Arbuckle, S., Thirukeswaran, S., Compton, A. G., Thorburn, D. R., Christodoulou, J. <strong>The expanding LARS2 phenotypic spectrum: HLASA, Perrault syndrome with leukodystrophy, and mitochondrial myopathy.</strong> Hum. Mutat. 41: 1425-1434, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32442335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32442335</a>] [<a href="https://doi.org/10.1002/humu.24050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32442335">Riley et al. (2020)</a> identified compound heterozygous missense mutations in the LARS2 gene: a.1313A-G transition, resulting in an asp438-to-gly (D438G) substitution in the editing domain, and R228H (<a href="#0011">604544.0011</a>) in the catalytic domain. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither was present in the gnomAD database. In vitro functional expression studies of these recombinant variants showed that both resulted in decreased LARS2 aminoacylation activity compared to controls, with R228H having a more severe effect than D438G. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32442335" 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 HYDROPS, LACTIC ACIDOSIS, AND SIDEROBLASTIC ANEMIA</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">rs1575240334 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1575240334;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=rs1575240334" 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=rs1575240334" 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 brothers, born of unrelated Middle Eastern parents (family 2), with hydrops, lactic acidosis, and sideroblastic anemia (HLASA; <a href="/entry/617021">617021</a>), <a href="#7" class="mim-tip-reference" title="Riley, L. G., Rudinger-Thirion, J., Frugier, M., Wilson, M., Luig, M., Alahakoon, T. I., Nixon, C. Y., Kirk, E. P., Roscioli, T., Lunke, S., Stark, Z., Wierenga, K. J., Palle, S., Walsh, M., Higgs, E., Arbuckle, S., Thirukeswaran, S., Compton, A. G., Thorburn, D. R., Christodoulou, J. <strong>The expanding LARS2 phenotypic spectrum: HLASA, Perrault syndrome with leukodystrophy, and mitochondrial myopathy.</strong> Hum. Mutat. 41: 1425-1434, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32442335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32442335</a>] [<a href="https://doi.org/10.1002/humu.24050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32442335">Riley et al. (2020)</a> identified compound heterozygous missense mutations in the LARS2 gene: a c.388G-A transition, resulting in an ala130-to-thr (A130T) substitution in the catalytic domain, and a c.2099C-T transition, resulting in a thr700-to-ile (T700I; <a href="#0014">604544.0014</a>) substitution in the anticodon binding domain. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither was present in the gnomAD database. In vitro functional expression studies of these recombinant variants showed that both resulted in decreased LARS2 aminoacylation activity compared to controls, with A130T having a more severe effect. One brother died on the first day of life, whereas the other survived but showed developmental delay and sensorineural hearing loss at 8 months of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32442335" 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>.0014 HYDROPS, LACTIC ACIDOSIS, AND SIDEROBLASTIC ANEMIA</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">rs1575308774 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1575308774;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=rs1575308774" 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=rs1575308774" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the c.2099C-T transition in the LARS2 gene, resulting in a thr700-to-ile (T700I) substitution, that was found in compound heterozygous state in 2 brothers (family 2) with hydrops, lactic acidosis, and sideroblastic anemia (HLASA; <a href="/entry/617021">617021</a>) by <a href="#7" class="mim-tip-reference" title="Riley, L. G., Rudinger-Thirion, J., Frugier, M., Wilson, M., Luig, M., Alahakoon, T. I., Nixon, C. Y., Kirk, E. P., Roscioli, T., Lunke, S., Stark, Z., Wierenga, K. J., Palle, S., Walsh, M., Higgs, E., Arbuckle, S., Thirukeswaran, S., Compton, A. G., Thorburn, D. R., Christodoulou, J. <strong>The expanding LARS2 phenotypic spectrum: HLASA, Perrault syndrome with leukodystrophy, and mitochondrial myopathy.</strong> Hum. Mutat. 41: 1425-1434, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32442335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32442335</a>] [<a href="https://doi.org/10.1002/humu.24050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32442335">Riley et al. (2020)</a>, see <a href="#0013">604544.0013</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32442335" 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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Bonnefond, L., Fender, A., Rudinger-Thirion, J., Giege, R., Florentz, C., Sissler, M.
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<strong>Toward the full set of human mitochondrial aminoacyl-tRNA synthetases: characterization of AspRS and TyrRS.</strong>
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Biochemistry 44: 4805-4816, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15779907/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15779907</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15779907" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1021/bi047527z" target="_blank">Full Text</a>]
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<div class="">
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<p class="mim-text-font">
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Kiss, H., Kedra, D., Yang, Y., Kost-Alimova, M., Kiss, C., O'Brien, K. P., Fransson, I., Klein, G., Imreh, S., Dumanski, J. P.
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<strong>A novel gene containing LIM domains (LIMD1) is located within the common eliminated region 1 (C3CER1) in 3p21.3.</strong>
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Hum. Genet. 105: 552-559, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10647888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10647888</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10647888" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s004399900188" target="_blank">Full Text</a>]
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</p>
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<a id="3" class="mim-anchor"></a>
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<a id="Kosaki2018" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Kosaki, R., Horikawa, R., Fujii, E., Kosaki, K.
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<strong>Biallelic mutations in LARS2 can cause Perrault syndrome type 2 with neurologic symptoms.</strong>
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Am. J. Med. Genet. 176A: 404-408, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29205794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29205794</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29205794" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.38552" target="_blank">Full Text</a>]
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</p>
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<a id="4" class="mim-anchor"></a>
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<a id="Lee2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Lee, S. S., Lee, R. Y. N., Fraser, A. G., Kamath, R. S., Ahringer, J., Ruvkun, G.
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<strong>A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity.</strong>
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Nature Genet. 33: 40-48, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12447374/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12447374</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12447374" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng1056" target="_blank">Full Text</a>]
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<li>
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<a id="5" class="mim-anchor"></a>
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<a id="Li2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Li, R., Guan, M.-X.
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<strong>Human mitochondrial leucyl-tRNA synthetase corrects mitochondrial dysfunctions due to the tRNA(Leu(UUR)) A3243G mutation, associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms and diabetes.</strong>
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Molec. Cell. Biol. 30: 2147-2154, 2010. Note: Erratum: Molec. Cell. Biol. 37: e00335-17, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20194621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20194621</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20194621[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=20194621" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1128/MCB.01614-09" target="_blank">Full Text</a>]
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<li>
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<a id="6" class="mim-anchor"></a>
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<a id="Pierce2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Pierce, S. B., Gersak, K., Michaelson-Cohen, R., Walsh, T., Lee, M. K., Malach, D., Klevit, R. E., King, M.-C., Levy-Lahad, E.
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<strong>Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome.</strong>
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Am. J. Hum. Genet. 92: 614-620, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23541342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23541342</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23541342[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=23541342" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2013.03.007" target="_blank">Full Text</a>]
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<a id="Riley2020" class="mim-anchor"></a>
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<p class="mim-text-font">
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Riley, L. G., Rudinger-Thirion, J., Frugier, M., Wilson, M., Luig, M., Alahakoon, T. I., Nixon, C. Y., Kirk, E. P., Roscioli, T., Lunke, S., Stark, Z., Wierenga, K. J., Palle, S., Walsh, M., Higgs, E., Arbuckle, S., Thirukeswaran, S., Compton, A. G., Thorburn, D. R., Christodoulou, J.
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<strong>The expanding LARS2 phenotypic spectrum: HLASA, Perrault syndrome with leukodystrophy, and mitochondrial myopathy.</strong>
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Hum. Mutat. 41: 1425-1434, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32442335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32442335</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32442335" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.24050" target="_blank">Full Text</a>]
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<a id="8" class="mim-anchor"></a>
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<a id="Riley2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Riley, L. G., Rudinger-Thirion, J., Schmitz-Abe, K., Thorburn, D. R., Davis, R. L., Teo, J., Arbuckle, S., Cooper, S. T., Campagna, D. R., Frugier, M., Markianos, K., Sue, C. M., Fleming, M. D., Christodoulou, J.
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<strong>LARS2 variants associated with hydrops, lactic acidosis, sideroblastic anemia, and multisystem failure.</strong>
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JIMD Rep. 28: 49-57, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26537577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26537577</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26537577[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=26537577" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/8904_2015_515" target="_blank">Full Text</a>]
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<a id="9" class="mim-anchor"></a>
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<a id="Solda2016" class="mim-anchor"></a>
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Solda, G., Caccia, S., Robusto, M., Chiereghin, C., Castorina, P., Ambrosetti, U., Duga, S., Asselta, R.
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<strong>First independent replication of the involvement of LARS2 in Perrault syndrome by whole-exome sequencing of an Italian family.</strong>
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J. Hum. Genet. 61: 295-300, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26657938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26657938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26657938[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=26657938" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/jhg.2015.149" target="_blank">Full Text</a>]
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<a id="10" class="mim-anchor"></a>
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<a id="Szeles1997" class="mim-anchor"></a>
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Szeles, A., Yang, Y., Sandlund, A. M., Kholodnyuck, I., Kiss, H., Kost-Alimova, M., Zabarovsky, E. R., Stanbridge, E., Klein, G., Imreh, S.
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<strong>Human/mouse microcell hybrid based on elimination test reduces the putative tumor suppressor region at 3p21.3 to 1.6 cM.</strong>
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Genes Chromosomes Cancer 20: 329-336, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9408748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9408748</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9408748" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="11" class="mim-anchor"></a>
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<a id="van der Knaap2019" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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van der Knaap, M. S., Bugiani, M., Mendes, M. I., Riley, L. G., Smith, D. E. C., Rudinger-Thirion, J., Frugier, M., Breur, M., Crawford, J., van Gaalen, J., Schouten, M., Willems, M., and 10 others.
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<strong>Biallelic variants in LARS2 and KARS cause deafness and (ovario)leukodystrophy.</strong>
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Neurology 92: e1225-e1237, 2019. Note: Electronic Article. Erratum: Neurology 93: 982 only, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30737337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30737337</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30737337[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=30737337" 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/10.1212/WNL.0000000000007098" target="_blank">Full Text</a>]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 01/07/2021
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 07/20/2016<br>Marla J. F. O'Neill - updated : 7/10/2013<br>Patricia A. Hartz - updated : 4/17/2012<br>Patricia A. Hartz - updated : 5/21/2009
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 2/11/2000
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alopez : 03/09/2023
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<span class="mim-text-font">
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alopez : 01/15/2021<br>ckniffin : 01/07/2021<br>carol : 09/11/2017<br>carol : 07/21/2016<br>carol : 07/20/2016<br>ckniffin : 07/20/2016<br>ckniffin : 07/19/2016<br>mcolton : 6/24/2015<br>alopez : 2/6/2015<br>joanna : 7/12/2013<br>carol : 7/10/2013<br>mgross : 9/20/2012<br>mgross : 5/14/2012<br>terry : 4/17/2012<br>mgross : 5/26/2009<br>terry : 5/21/2009<br>mgross : 2/11/2000
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<strong>*</strong> 604544
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<h3>
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LEUCYL-tRNA SYNTHETASE 2; LARS2
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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LEUCYL-tRNA SYNTHETASE, MITOCHONDRIAL<br />
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MITOCHONDRIAL LEURS
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: LARS2</em></strong>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 1237349008;
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</span>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 3p21.31
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Genomic coordinates <span class="small">(GRCh38)</span> : 3:45,388,576-45,549,407 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</div>
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|
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|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
3p21.31
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Hydrops, lactic acidosis, and sideroblastic anemia
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
617021
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Perrault syndrome 4
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
615300
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>The LARS2 gene encodes mitochondrial leucyl-tRNA synthetase (summary by Solda et al., 2016). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>By searching databases for aminoacyl-tRNA synthetases containing a mitochondrial targeting sequence, Bonnefond et al. (2005) identified LARS2, which they called mitochondrial LEURS. The deduced 903-amino acid protein has an N-terminal mitochondrial targeting signal that is cleaved after residue 39. LARS2 has characteristics of a class I aminoacyl-tRNA synthetase, including a classical Rossmann fold. </p><p>Using Northern blot analysis, Li and Guan (2010) detected ubiquitous but variable LARS2 expression, with highest expression in tissues with high metabolic rates, such as skeletal muscle, heart, and kidney. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Bonnefond et al. (2005) determined that the LARS2 gene contains 20 exons and spans 153 kb. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Szeles et al. (1997) used an experimental system, the elimination test, to identify a 1-Mb segment commonly lost in chromosomal deletions on 3p in a large number of human tumors. The region was referred to as the chromosome 3 common eliminated region-1, or C3CER1. Using the sequence of 2 overlapping PACs from C3CER1, Kiss et al. (1999) localized the cDNA encoding the precursor of mitochondrial leucyl-tRNA synthetase to the 3p21.3 region. They localized a second gene, LIMD1 (604543), very close to the LARS2 gene. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>The 3243A-G mutation (590050.0001) in tRNA-leu(UUR) (MTTL1; 590050), where R = A or G, causes MELAS syndrome (540000). The primary defect with this mutation is inefficient aminoacylation of mutant tRNA-leu(UUR), causing mitochondrial dysfunction with reduced rate of RNA processing and protein synthesis and defects in respiration. From human cytoplasmic hybrids (cybrids) containing 3243A-G mutant or wildtype mitochondria from heteroplasmic MELAS patient myoblasts, Li and Guan (2010) developed a nearly homoplastic mutant cybrid line and an isogenic homoplastic wildtype cybrid line. They found that overexpression of LARS2 in the mutant cybrid line, but not the wildtype cybrid line, increased the steady-state level of aminoacylated tRNA-leu(UUR) and the rate of RNA processing and translation and restored mitochondrial respiration. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Perrault Syndrome 4</em></strong></p><p>
|
|
In affected individuals with Perrault syndrome-4 (PRLTS4; 615300) from a consanguineous family of Palestinian ancestry and a family of Slovenian ancestry, Pierce et al. (2013) identified homozygous and compound heterozygous mutations in the LARS2 gene (604544.0001-604544.0003, respectively). </p><p>In a sister and brother, born of unrelated Italian parents, with PRLTS4, Solda et al. (2016) identified compound heterozygous missense mutations in the LARS2 gene (T300M, 604544.0004 and E638K, 603544.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional studies and studies of patient cells were not performed. </p><p>In 2 Japanese sisters with PRLTS4, Kosaki et al. (2018) identified compound heterozygous missense mutations in the LARS2 gene (E294K, 604655.0007 and T519M, 604544.0008). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither variant was found among 2,049 Japanese controls, but both were found at very low frequencies in the ExAC database. Functional studies of the variants were not performed, but they were considered likely pathogenic according to ACMG criteria. The patients also had neurodevelopmental abnormalities with learning difficulties and behavioral abnormalities, thus expanding the phenotypic spectrum of PRLTS4. </p><p>In 4 unrelated patients, 2 females and 2 males, with PRLTS4, van der Knaap et al. (2019) identified compound heterozygous mutations in the LARS2 gene (see, e.g., 604544.0007; 604544.0009-604544.0011). The mutations, which were found by whole-genome or whole-exome sequencing, segregated with the disorder in all patients from whom parental DNA was available. Patient-derived mitochondria showed decreased LARS2 aminoacylation activity (about 50% of controls). In addition to deafness and ovarian failure (in the females), the patients had neurologic involvement, both behavioral and motor, as well as leukodystrophy on brain imaging. </p><p><strong><em>Hydrops, Lactic Acidosis, and Sideroblastic Anemia</em></strong></p><p>
|
|
In a female infant, born of unrelated Pakistani parents, with hydrops, lactic acidosis, and sideroblastic anemia (HLASA; 617021) resulting in death at age 5 days, Riley et al. (2016) identified compound heterozygous missense mutations in the LARS2 gene (T522N, 604544.0001 and A430V, 604544.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies in E. coli showed that the variants resulted in variable decreases in catalytic activity. </p><p>In 3 boys from 2 unrelated families (families 1 and 2) with HLASA, Riley et al. (2020) identified compound heterozygous missense mutations in the LARS2 gene (604544.0011-604544.0014). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. None was present in the gnomAD database. In vitro functional expression studies of these recombinant variants showed that all resulted in decreased LARS2 aminoacylation activity compared to controls, although some had more severe effects on enzyme activity than others. The authors postulated that the degree of impaired enzyme activity correlated with the severity of the phenotype, such that HLASA-associated LARS2 mutations have a more detrimental effect compared to PRLTS4-associated mutations. However, there is a phenotypic spectrum with overlapping clinical features between the 2 disorders. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
|
|
Riley et al. (2020) reported a 17-year-old boy with a reversible mitochondrial myopathy associated with compound heterozygous missense variants in the LARS2 gene (R103H and D518N). The variants, which were found by exome sequencing and confirmed by Sanger sequencing, were each inherited from an unaffected parent. Both were found in the gnomAD database: R103H had a frequency of 1.6 x 10(-5), whereas R518N had a frequency of 0.0039; there were 6 homozygous carriers of R518N in gnomAD. The patient presented in infancy with mildly delayed motor development and pronounced neck muscle weakness. Later in childhood, he had hypotonia, limb muscle weakness, positive Gowers sign, and awkward running. By adolescence, structured exercise programs improved his stamina and he was able to participate in sports. At age 17 years, he had normal muscle bulk and strength with negative Gowers sign. Cognitive function, hearing, and vision were normal. Laboratory studies were notable for increased blood lactate and creatine kinase. Muscle biopsy showed variation in fiber size with a reduction in type 1 fibers, mildly increased central nuclei, and abnormal subsarcolemmal accumulation of enlarged pleiomorphic mitochondria, consistent with a mitochondrial myopathy. Analysis of muscle mitochondrial respiratory chain complexes showed isolated low complex I activity compared to controls. LARS2 protein levels were decreased in patient muscle (20% of controls), but normal in fibroblasts. In vitro studies showed that LARS2 aminoacylation catalytic efficiency was reduced for each mutant (a 2-fold loss for R103H and a 6-fold loss for D518N); enzymatic activity for R103H was particularly low when ATP concentrations were decreased. The authors noted the unusual phenotype associated with LARS2 variants. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>To identify in a systematic manner all of the gene classes that control C. elegans life span, Lee et al. (2003) used a set of more than 5,600 genes in an RNA interference (RNAi) screen to identify genes that extend life span when inactivated. The screen showed that a large number of genes essential for mitochondrial function have critical roles in determining C. elegans life span. Consistent with these results, in a classic genetic screen for increased life span, they found that a probable null mutation in a mitochondrial leucyl-tRNA synthetase gene, Lrs2, resulted in a markedly longer life span. Long-lived worms with impaired mitochondria had lower ATP content and oxygen consumption, but differential responses to free-radical and other stresses. These data suggested that the longer life span cannot simply be assigned to lower free radical production and suggested a more complex coupling of metabolism and longevity. </p><p>Pierce et al. (2013) confirmed that a C. elegans strain homozygous for a null mutation (T247X) in LARS2 are completely sterile and produce no progeny at all, in contrast to wildtype worms that produce 200 to 250 progeny per animal. Germ cell development was arrested, such that oocytes were never observed. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>14 Selected Examples):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 PERRAULT SYNDROME 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
HYDROPS, LACTIC ACIDOSIS, AND SIDEROBLASTIC ANEMIA, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LARS2, THR522ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs199589947,
|
|
|
|
|
|
gnomAD: rs199589947,
|
|
|
|
|
|
ClinVar: RCV000049285, RCV000235552, RCV000520936, RCV000604453, RCV000857234, RCV004689437, RCV004730866
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Perrault Syndrome 4</em></strong></p><p>
|
|
In a sister and 2 brothers with Perrault syndrome (PRLTS4; 615300) from a consanguineous family of Palestinian ancestry, Pierce et al. (2013) identified homozygosity for a c.1565C-A transversion at chr3:45,537,808C-A (GRCh37) in the LARS2 gene, resulting in a thr522-to-asn (T522N) substitution at a highly conserved residue in the catalytic domain, located at the N-terminal end of an alpha-helix that forms part of a pocket into which the 3-prime end of the tRNA strand binds. The mutation was present in heterozygosity in their unaffected parents, but was not found in 239 Palestinian or 362 Slovenian controls, or in 6,500 controls of European American or African American ancestry in the NHLBI Exome Variant Server. Functional analysis in a yeast complementation assay showed only partial rescue of red pigment production with the T522N variant, indicating reduced activity relative to wildtype. </p><p><strong><em>Hydrops, Lactic Acidosis, and Sideroblastic Anemia</em></strong></p><p>
|
|
In a female infant, born of unrelated Pakistani parents, with hydrops, lactic acidosis, and sideroblastic anemia (HLASA; 617021) resulting in death at age 5 days, Riley et al. (2016) identified compound heterozygous missense mutations in the LARS2 gene: a T522N substitution in the catalytic domain, and a c.1289C-T transition, resulting in an ala430-to-val (A430V) substitution (604544.0006) at a partially conserved residue in the CP1 editing domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and were not found in the Exome Variant Server database or in 345 controls exomes. A430V was not found in the ExAC database, whereas T522N was found at a low frequency (0.0002). In vitro functional expression studies in E. coli showed that the A430V variant resulted in an 18-fold loss of catalytic activity, whereas the T522N variant resulted in a 9-fold reduction compared to wildtype. Immunoblot analysis showed normal levels of LARS2 in patient muscle, but about a 50% decrease in patient liver. Levels of mitochondrial complex proteins, particularly complex I, were decreased in patient liver and less so in patient muscle, but not in patient fibroblasts. There was no defect in mitochondrial protein synthesis in patient fibroblasts or induced myotubes, suggesting that the variants only affect tissue with higher energy demands. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 PERRAULT SYNDROME 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LARS2, THR629MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs398123036,
|
|
|
|
|
|
gnomAD: rs398123036,
|
|
|
|
|
|
ClinVar: RCV000049286, RCV001544530, RCV002513678
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a woman of Slovenian ancestry with premature ovarian failure and severe hearing loss (PRLTS4; 615300), Pierce et al. (2013) identified compound heterozygosity for 2 mutations in the LARS2 gene: a c.1866C-T transition at chr3:45,557,610 (GRCh37), resulting in a thr629-to-met (T629M) substitution at a residue conserved in mammals, and a 1-bp deletion (c.1077delT; 604544.0003) at chr3:45,527,241 (GRCh37), predicted to yield a 373-amino acid truncated protein with 14 novel amino acids at the C terminus (Ile360PhefsTer15). Her unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in 239 Palestinian or 362 Slovenian controls, or in 6,500 controls of European American or African American ancestry in the NHLBI Exome Variant Server. Functional analysis in a yeast complementation assay showed no rescue of red pigment production with the 1077delT variant, indicating that it represents a nonfunctional variant; in contrast, the T629M variant produced enough activity to support wildtype production of red pigment. Pierce et al. (2013) suggested that the compound heterozygous combination of LARS2 T629M and 1077delT yields reduced total LARS2 activity, resulting in inadequate mitochondrial function in the ovary and inner ear. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 PERRAULT SYNDROME 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LARS2, 1-BP DEL, 1077T
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs398123037,
|
|
|
|
|
|
|
|
ClinVar: RCV000049287, RCV002513679
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 1-bp deletion in the LARS2 gene (c.1077delT) that was found in compound heterozygous state in a woman with premature ovarian failure and severe hearing loss (PRLTS4; 615300) by Pierce et al. (2013), see 604544.0002. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 PERRAULT SYNDROME 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LARS2, THR300MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs864309642,
|
|
|
|
|
|
gnomAD: rs864309642,
|
|
|
|
|
|
ClinVar: RCV000203256, RCV000203257, RCV003556221
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a brother and sister, born of unrelated Italian parents, with Perrault syndrome-4 (PRLTS4; 615300), Solda et al. (2016) identified compound heterozygous missense mutations in the LARS2 gene: a c.899C-T transition (c.899C-T, NM_015340.3), resulting in a thr300-to-met (T300M) substitution in the editing domain, and a c.1912G-A transition, resulting in a glu638-to-lys (E638K; 604655.0005) substitution in the catalytic domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were filtered against the dbSNP (build 135), 1000 Genomes Project, and Exome Sequencing Project databases, and segregated with the disorder in the family. The mutations were not found in the ExAC database or in an in-house database of 3,500 ethnically matched controls. The E638 residue is highly conserved, whereas the T300 residue is conserved in mammals, but not in more distantly related species. Molecular modeling based on the E. coli structure suggested that both mutations would be deleterious. In vitro functional studies and studies on patient cells were not performed. </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>
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<span class="mim-font">
|
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<strong>.0005 PERRAULT SYNDROME 4</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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LARS2, GLU638LYS
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|
<br />
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|
|
SNP: rs864309643,
|
|
|
|
|
|
|
|
ClinVar: RCV000203255
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
<div>
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<span class="mim-text-font">
|
|
<p>For discussion of the c.1912G-A transition (c.1912G-A, NM_015340.3) in the LARS2 gene, resulting in a glu638-to-lys (E638K) substitution, that was found in compound heterozygous state in 2 sibs with Perrault syndrome-4 (PRLTS4; 615300) by Solda et al. (2016), see 604655.0004. </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>.0006 HYDROPS, LACTIC ACIDOSIS, AND SIDEROBLASTIC ANEMIA (1 patient)</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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LARS2, ALA430VAL
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<br />
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SNP: rs879255606,
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ClinVar: RCV000235638
|
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|
</span>
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|
</div>
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<div>
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<span class="mim-text-font">
|
|
<p>For discussion of the c.1289C-T transition (c.1289C-T, NM_015349.3) in the LARS2 gene, resulting in an ala430-to-val (A430V) substitution, that was found in compound heterozygous state in a patient with hydrops, lactic acidosis, and sideroblastic anemia (HLASA; 617021) by Riley et al. (2016), see 604544.0001. </p>
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|
</span>
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|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0007 PERRAULT SYNDROME 4</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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LARS2, GLU294LYS
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<br />
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SNP: rs749627411,
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|
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gnomAD: rs749627411,
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ClinVar: RCV001283750, RCV001587314, RCV002542964
|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 Japanese sisters with Perrault syndrome-4 (PRLTS4; 615300), Kosaki et al. (2018) identified compound heterozygous missense mutations in the LARS2 gene: a c.880G-A transition (c.880G-A, NM_015340) in exon 10, resulting in a glu294-to-lys (E294K) substitution, and a c.1556C-T transition in exon 14, resulting in a thr519-to-met (T519M; 604544.0008) substitution. Both mutations occurred in the editing domain of the tRNA synthetase. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither variant was found among 2,049 Japanese controls, but both were found at very low frequencies in the ExAC database. Functional studies of the variants were not performed, but they were considered likely pathogenic according to ACMG criteria. The patients also had neurodevelopmental abnormalities with learning difficulties and behavioral abnormalities, thus expanding the phenotypic spectrum of PRLTS4. </p><p>In a 48-year-old woman (patient 4) with PRLTS4, van der Knaap et al. (2019) identified compound heterozygosity for the E294K mutation and R228H (see 604544.0011). The mutations were found by exome sequencing: E294K was present at a low frequency (0.0016%) in the gnomAD database. Patient-derived mitochondria showed decreased LARS2 aminoacylation activity (about 50% of controls). In addition to deafness and ovarian failure, the patient developed progressive neurologic motor abnormalities as an adult that were associated with leukodystrophy on brain imaging. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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|
</div>
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|
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|
<div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 PERRAULT SYNDROME 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
LARS2, THR519MET
|
|
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|
<br />
|
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|
|
SNP: rs141097216,
|
|
|
|
|
|
gnomAD: rs141097216,
|
|
|
|
|
|
ClinVar: RCV001283751, RCV001760324, RCV002537926
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.1556C-T transition (c.1556C-T, NM_015340) in exon 14 of the LARS2 gene, resulting in a thr519-to-met (T519M) substitution, that was found in compound heterozygous state in 2 sisters with Perrault syndrome-4 (PRLTS4; 615300) by Kosaki et al. (2018), see 604544.0007. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 PERRAULT SYNDROME 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LARS2, ARG663TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs774649299,
|
|
|
|
|
|
gnomAD: rs774649299,
|
|
|
|
|
|
ClinVar: RCV000496181, RCV003441896
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 37-year-old man (patient 2) with Perrault syndrome-4 (PRLTS4; 615300), van der Knaap et al. (2019) identified compound heterozygous missense mutations in the LARS2 gene: a c.1987C-T transition (c.1987C-T, NM_015340.3), resulting in an arg663-to-trp (R663W) substitution between the catalytic and tRNA-binding domains, and a c.371A-T transversion, resulting in an asn124-to-ile (N124I; 604544.0010) substitution in the catalytic domain. Both mutations occurred at conserved residues. The mutations, which were found by whole-exome sequencing, were each inherited from an unaffected parent. The R663W variant was found at a low frequency (0.0012%) in the gnomAD database, whereas N124I was not present. In vitro functional expression studies of purified recombinant variants showed a 3-fold loss of LARS2 catalytic aminoacylation activity compared to controls. Binding to tRNA was not affected by the mutations. Patient-derived mitochondria also showed decreased LARS2 activity (about 50% of controls) without effects on mitochondrial respiratory chain complexes. In addition to deafness, the patient had progressive neurologic abnormalities, both behavioral and motor, and leukodystrophy on brain imaging. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 PERRAULT SYNDROME 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LARS2, ASN124ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs776171893,
|
|
|
|
|
|
gnomAD: rs776171893,
|
|
|
|
|
|
ClinVar: RCV000496108
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.371A-T transversion (c.371A-T, NM_015340.3) in the LARS2 gene, resulting in an asn124-to-ile (N124I) substitution, that was found in compound heterozygous state in a patient with Perrault syndrome-4 (PRLTS4; 615300) by van der Knaap et al. (2019), see 604544.0009. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 PERRAULT SYNDROME 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
HYDROPS, LACTIC ACIDOSIS, AND SIDEROBLASTIC ANEMIA, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LARS2, ARG228HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs770440975,
|
|
|
|
|
|
|
|
ClinVar: RCV000993581, RCV001283752, RCV002538373
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Perrault Syndrome 4</em></strong></p><p>
|
|
In a 48-year-old woman (patient 4) with Perrault syndrome-4 (PRLTS4; 615300), van der Knaap et al. (2019) identified compound heterozygous missense mutations in the LARS2 gene: a c.683G-A transition (c.683G-A, NM_015340.3), resulting in an arg228-to-his (R228H) substitution in the catalytic domain, and E294K (604544.0007). The R228H was not present in the gnomAD database. The mutations were found by whole-exome sequencing; the patient's unaffected mother carried the R228H variant, but DNA from the father was not available. Patient-derived mitochondria showed decreased LARS2 aminoacylation activity (about 50% of controls). In addition to deafness and ovarian failure, the patient developed progressive neurologic motor abnormalities as an adult that were associated with leukodystrophy on brain imaging. </p><p><strong><em>Hydrops, Lactic Acidosis, and Sideroblastic Anemia</em></strong></p><p>
|
|
In an 18-month-old boy (patient 1) with hydrops, lactic acidosis, and sideroblastic anemia (HLASA; 617021), Riley et al. (2020) identified compound heterozygous missense mutations in the LARS2 gene: R228H and D438G (604544.0012). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither was present in the gnomAD database. In vitro functional expression studies of these recombinant variants showed that both resulted in decreased LARS2 aminoacylation activity compared to controls, with R228H having a more severe effect than D438G. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 HYDROPS, LACTIC ACIDOSIS, AND SIDEROBLASTIC ANEMIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LARS2, ASP438GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1575289366,
|
|
|
|
|
|
|
|
ClinVar: RCV000993582
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 18-month-old boy, born of Japanese and Caucasian parents (family 1), with hydrops, lactic acidosis, and sideroblastic anemia (HLASA; 617021), Riley et al. (2020) identified compound heterozygous missense mutations in the LARS2 gene: a.1313A-G transition, resulting in an asp438-to-gly (D438G) substitution in the editing domain, and R228H (604544.0011) in the catalytic domain. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither was present in the gnomAD database. In vitro functional expression studies of these recombinant variants showed that both resulted in decreased LARS2 aminoacylation activity compared to controls, with R228H having a more severe effect than D438G. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 HYDROPS, LACTIC ACIDOSIS, AND SIDEROBLASTIC ANEMIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LARS2, ALA130THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1575240334,
|
|
|
|
|
|
|
|
ClinVar: RCV000993583
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 brothers, born of unrelated Middle Eastern parents (family 2), with hydrops, lactic acidosis, and sideroblastic anemia (HLASA; 617021), Riley et al. (2020) identified compound heterozygous missense mutations in the LARS2 gene: a c.388G-A transition, resulting in an ala130-to-thr (A130T) substitution in the catalytic domain, and a c.2099C-T transition, resulting in a thr700-to-ile (T700I; 604544.0014) substitution in the anticodon binding domain. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither was present in the gnomAD database. In vitro functional expression studies of these recombinant variants showed that both resulted in decreased LARS2 aminoacylation activity compared to controls, with A130T having a more severe effect. One brother died on the first day of life, whereas the other survived but showed developmental delay and sensorineural hearing loss at 8 months of age. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 HYDROPS, LACTIC ACIDOSIS, AND SIDEROBLASTIC ANEMIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LARS2, THR700ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1575308774,
|
|
|
|
|
|
|
|
ClinVar: RCV000993584
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.2099C-T transition in the LARS2 gene, resulting in a thr700-to-ile (T700I) substitution, that was found in compound heterozygous state in 2 brothers (family 2) with hydrops, lactic acidosis, and sideroblastic anemia (HLASA; 617021) by Riley et al. (2020), see 604544.0013. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bonnefond, L., Fender, A., Rudinger-Thirion, J., Giege, R., Florentz, C., Sissler, M.
|
|
<strong>Toward the full set of human mitochondrial aminoacyl-tRNA synthetases: characterization of AspRS and TyrRS.</strong>
|
|
Biochemistry 44: 4805-4816, 2005.
|
|
|
|
|
|
[PubMed: 15779907]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1021/bi047527z]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Kiss, H., Kedra, D., Yang, Y., Kost-Alimova, M., Kiss, C., O'Brien, K. P., Fransson, I., Klein, G., Imreh, S., Dumanski, J. P.
|
|
<strong>A novel gene containing LIM domains (LIMD1) is located within the common eliminated region 1 (C3CER1) in 3p21.3.</strong>
|
|
Hum. Genet. 105: 552-559, 1999.
|
|
|
|
|
|
[PubMed: 10647888]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s004399900188]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Kosaki, R., Horikawa, R., Fujii, E., Kosaki, K.
|
|
<strong>Biallelic mutations in LARS2 can cause Perrault syndrome type 2 with neurologic symptoms.</strong>
|
|
Am. J. Med. Genet. 176A: 404-408, 2018.
|
|
|
|
|
|
[PubMed: 29205794]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.a.38552]
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<strong>Human mitochondrial leucyl-tRNA synthetase corrects mitochondrial dysfunctions due to the tRNA(Leu(UUR)) A3243G mutation, associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms and diabetes.</strong>
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Pierce, S. B., Gersak, K., Michaelson-Cohen, R., Walsh, T., Lee, M. K., Malach, D., Klevit, R. E., King, M.-C., Levy-Lahad, E.
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van der Knaap, M. S., Bugiani, M., Mendes, M. I., Riley, L. G., Smith, D. E. C., Rudinger-Thirion, J., Frugier, M., Breur, M., Crawford, J., van Gaalen, J., Schouten, M., Willems, M., and 10 others.
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