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Entry
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- *604733 - TRYPTOPHANYL-tRNA SYNTHETASE 2; WARS2
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- OMIM
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<p>
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<span class="h4">*604733</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<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/604733">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 role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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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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<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 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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<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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<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=ENSG00000116874;t=ENST00000235521" 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=10352" 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=604733" 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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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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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=ENSG00000116874;t=ENST00000235521" 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_001378226,NM_001378227,NM_001378228,NM_001378229,NM_001378230,NM_001378231,NM_015836,NM_201263,XM_005270350,XM_017000038,XM_024449826,XM_024449860,XM_047429105" 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_015836" 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=604733" 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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<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=05295&isoform_id=05295_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/WARS2" 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/6572289,7710154,21362967,28278717,41352700,62897955,119577097,119577098,189053974,221041154,221041514,221042772,221043152,530361552,1034554651,1370451535,1370451537,1804891951,1804891955,1804891971,1804891986,1804891998,1804892010,2217263134,2462502111,2462502113,2462502115,2462502117" 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/Q9UGM6" 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 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=10352" 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=ENSG00000116874;t=ENST00000235521" 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=WARS2" 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=WARS2" 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+10352" 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/WARS2" 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:10352" 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/10352" 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=chr1&hgg_gene=ENST00000235521.5&hgg_start=119031216&hgg_end=119140672&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 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:12730" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=604733[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=604733[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/ENSG00000116874" 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=WARS2" 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=WARS2" 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=WARS2" 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=WARS2&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/PA37341" 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:12730" 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/FBgn0036763.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:1917810" 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/WARS2#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:1917810" 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/10352/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=10352" 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=WBGene00006946;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-050306-26" 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:10352" 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=WARS2&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> 1260128008<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>
|
|
604733
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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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TRYPTOPHANYL-tRNA SYNTHETASE 2; WARS2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
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TRYPTOPHANYL-tRNA SYNTHETASE, MITOCHONDRIAL<br />
|
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MITOCHONDRIAL TRPRS
|
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</span>
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=WARS2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">WARS2</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/1/971?start=-3&limit=10&highlight=971">1p12</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:119031216-119140672&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'})">1:119,031,216-119,140,672</a> </span>
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</div>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
|
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Location
|
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</th>
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<th>
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|
Phenotype
|
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=617710,619738" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
|
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</th>
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<th>
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|
Phenotype <br /> MIM number
|
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</th>
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<th>
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Inheritance
|
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</th>
|
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
|
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</tr>
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</thead>
|
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<tbody>
|
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<tr>
|
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<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/1/971?start=-3&limit=10&highlight=971">
|
|
1p12
|
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</a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
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|
<a href="/entry/617710"> 617710 </a>
|
|
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
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|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<tr>
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<td>
|
|
<span class="mim-font">
|
|
Parkinsonism-dystonia 3, childhood-onset
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/619738"> 619738 </a>
|
|
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
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</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>
|
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</table>
|
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
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<p>Tryptophanyl-tRNA synthetases are essential enzymes that catalyze the aminoacylation of tRNA(trp) with tryptophan. Two forms of tryptophanyl-tRNA synthetase exist, a cytoplasmic form, named WARS (<a href="/entry/191050">191050</a>), and a mitochondrial form, named WARS2 (<a href="#6" class="mim-tip-reference" title="Martinez-Dominguez, M. T., Justesen, J., Kruse, T. A., Hansen, L. L. <strong>Assignment of the human mitochondrial tryptophanyl-tRNA synthetase (WARS2) to 1p13.3-p13.1 by radiation hybrid mapping.</strong> Cytogenet. Cell Genet. 83: 249-250, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10072595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10072595</a>] [<a href="https://doi.org/10.1159/000015196" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10072595">Martinez-Dominguez et al., 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10072595" 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 homology searching of an EST database, <a href="#6" class="mim-tip-reference" title="Martinez-Dominguez, M. T., Justesen, J., Kruse, T. A., Hansen, L. L. <strong>Assignment of the human mitochondrial tryptophanyl-tRNA synthetase (WARS2) to 1p13.3-p13.1 by radiation hybrid mapping.</strong> Cytogenet. Cell Genet. 83: 249-250, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10072595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10072595</a>] [<a href="https://doi.org/10.1159/000015196" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10072595">Martinez-Dominguez et al. (1998)</a> identified a WARS2 EST. The deduced WARS2 protein contains a signal peptide for mitochondrial import. WARS2 is highly homologous to bacterial tryptophanyl-tRNA synthetases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10072595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By searching databases for aminoacyl-tRNA synthetases containing a mitochondrial targeting sequence, <a href="#1" class="mim-tip-reference" title="Bonnefond, L., Fender, A., Rudinger-Thirion, J., Giege, R., Florentz, C., Sissler, M. <strong>Toward the full set of human mitochondrial aminoacyl-tRNA synthetases: characterization of AspRS and TyrRS.</strong> Biochemistry 44: 4805-4816, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15779907/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15779907</a>] [<a href="https://doi.org/10.1021/bi047527z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15779907">Bonnefond et al. (2005)</a> identified WARS2, which they called mitochondrial TRPRS. The deduced 360-amino acid protein has an N-terminal mitochondrial targeting signal that is cleaved after residue 18. WARS2 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><a href="#7" class="mim-tip-reference" title="Musante, L., Puttmann, L., Kahrizi, K., Garshasbi, M., Hu, H., Stehr, H., Lipkowitz, B., Otto, S., Jensen, L. R., Tzschach, A., Jamali, P., Wienker, T., Najmabadi, H., Ropers, H. H., Kuss, A. W. <strong>Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability.</strong> Hum. Mutat. 38: 621-636, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28236339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28236339</a>] [<a href="https://doi.org/10.1002/humu.23205" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28236339">Musante et al. (2017)</a> found expression of the WARS2 gene in multiple brain regions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28236339" 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 WARS2 gene contains 6 exons and spans 109 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15779907" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By analysis of a radiation hybrid mapping panel, <a href="#6" class="mim-tip-reference" title="Martinez-Dominguez, M. T., Justesen, J., Kruse, T. A., Hansen, L. L. <strong>Assignment of the human mitochondrial tryptophanyl-tRNA synthetase (WARS2) to 1p13.3-p13.1 by radiation hybrid mapping.</strong> Cytogenet. Cell Genet. 83: 249-250, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10072595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10072595</a>] [<a href="https://doi.org/10.1159/000015196" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10072595">Martinez-Dominguez et al. (1998)</a> mapped the WARS2 gene to chromosome 1p13.3-p13.1, between markers D1S453 and D1S514. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10072595" 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="#9" class="mim-tip-reference" title="Stumpf, A. M. <strong>Personal Communication.</strong> Baltimore, Md. 02/17/2022."None>Stumpf (2022)</a> mapped the WARS2 gene to chromosome 1p12 based on an alignment of the WARS2 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AK313740" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AK313740</a>) with the genomic sequence (GRCh38).</p>
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<p><strong><em>Mitochondrial Neurodevelopmental Disorder with Abnormal Movements and Lactic Acidosis with or without Seizures</em></strong></p><p>
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In 2 sisters, born of consanguineous Iranian parents (family 2), with mitochondrial neurodevelopmental disorder with abnormal movements and lactic acidosis with or without seizures (NEMMLAS; <a href="/entry/617710">617710</a>), <a href="#7" class="mim-tip-reference" title="Musante, L., Puttmann, L., Kahrizi, K., Garshasbi, M., Hu, H., Stehr, H., Lipkowitz, B., Otto, S., Jensen, L. R., Tzschach, A., Jamali, P., Wienker, T., Najmabadi, H., Ropers, H. H., Kuss, A. W. <strong>Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability.</strong> Hum. Mutat. 38: 621-636, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28236339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28236339</a>] [<a href="https://doi.org/10.1002/humu.23205" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28236339">Musante et al. (2017)</a> identified compound heterozygous mutations in the WARS2 gene (c.325delC, <a href="#0001">604733.0001</a> and W13G, <a href="#0002">604733.0002</a>). The mutations, which were found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies showed that the W13G mutation resulted in impaired localization of the WARS2 mutant protein to the mitochondria. <a href="#7" class="mim-tip-reference" title="Musante, L., Puttmann, L., Kahrizi, K., Garshasbi, M., Hu, H., Stehr, H., Lipkowitz, B., Otto, S., Jensen, L. R., Tzschach, A., Jamali, P., Wienker, T., Najmabadi, H., Ropers, H. H., Kuss, A. W. <strong>Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability.</strong> Hum. Mutat. 38: 621-636, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28236339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28236339</a>] [<a href="https://doi.org/10.1002/humu.23205" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28236339">Musante et al. (2017)</a> suggested that the W13G variant may be a hypomorphic polymorphism that becomes significant only when paired with a loss-of-function allele. Of note, overexpression of wildtype WARS2 resulted in decreased SDHA (<a href="/entry/600857">600857</a>) compared to cells overexpressing the mutant protein; SDHA is part of the mitochondrial respiratory chain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28236339" 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 24-year-old man with NEMMLAS, <a href="#10" class="mim-tip-reference" title="Theisen, B. E., Rumyantseva, A., Cohen, J. S., Alcaraz, W. A., Shinde, D. N., Tang, S., Srivastava, S., Pevsner, J., Trifunovic, A., Fatemi, A. <strong>Deficiency of WARS2, encoding mitochondrial tryptophanyl tRNA synthetase, causes severe infantile onset leukoencephalopathy.</strong> Am. J. Med. Genet. 173A: 2505-2510, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28650581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28650581</a>] [<a href="https://doi.org/10.1002/ajmg.a.38339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28650581">Theisen et al. (2017)</a> identified compound heterozygous mutations in the WARS2 gene (K313M, <a href="#0003">604733.0003</a> and c.298_300delCTT, <a href="#0004">604733.0004</a>). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Patient fibroblasts showed decreased de novo synthesis of proteins within the mitochondria, leading to significantly decreased steady-state levels of respiratory chain subunits and lower oxygen consumption rates compared to controls (about 30%). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28650581" 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 6 patients from 5 unrelated families with NEMMLAS, <a href="#11" class="mim-tip-reference" title="Wortmann, S. B., Timal, S., Venselaar, H., Wintjes, L. T., Kopajtich, R., Feichtinger, R. G., Onnekink, C., Mulmeister, M., Brandt, U., Smeitink, J. A., Veltman, J. A., Sperl, W., and 12 others. <strong>Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy.</strong> Hum. Mutat. 38: 1786-1795, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28905505/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28905505</a>] [<a href="https://doi.org/10.1002/humu.23340" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28905505">Wortmann et al. (2017)</a> identified homozygous or compound heterozygous mutations in the WARS2 gene (see, e.g., <a href="#0003">604733.0003</a>; <a href="#0005">604733.0005</a>-<a href="#0007">604733.0007</a>). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. There were 6 missense mutations, 1 frameshift, and 1 insertion/deletion. Cells derived from several unrelated patients showed decreased or absent WARS2 protein levels compared to controls. In addition, cells derived from 2 sibs showed a clear decrease in charged mt-tRNA(Trp), while total mt-tRNA(Trp) levels appeared normal. These findings suggested that the defect in WARS2 causes improper aminoacylation of tRNA(Trp), leading to abnormalities in mitochondrial oxidative phosphorylation (OXPHOS) protein synthesis. However, OXPHOS activities in most patient cells were normal, with the exception of 1 severely affected individual and mild changes in some tissues of 2 other patients. <a href="#11" class="mim-tip-reference" title="Wortmann, S. B., Timal, S., Venselaar, H., Wintjes, L. T., Kopajtich, R., Feichtinger, R. G., Onnekink, C., Mulmeister, M., Brandt, U., Smeitink, J. A., Veltman, J. A., Sperl, W., and 12 others. <strong>Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy.</strong> Hum. Mutat. 38: 1786-1795, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28905505/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28905505</a>] [<a href="https://doi.org/10.1002/humu.23340" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28905505">Wortmann et al. (2017)</a> postulated that the OXPHOS defect may be apparent in the central nervous system, but such tissue was not available for study. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28905505" 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 sisters, born of unrelated Swedish parents, with NEMMLAS, <a href="#5" class="mim-tip-reference" title="Maffezzini, C., Laine, I., Dallabona, C., Clemente, P., Calvo-Garrido, J., Wibom, R., Naess, K., Barbaro, M., Falk, A., Donnini, C., Freyer, C., Wredenberg, A., Wedell, A. <strong>Mutations in the mitochondrial tryptophanyl-tRNA synthetase cause growth retardation and progressive leukoencephalopathy.</strong> Molec. Genet. Genomic Med. 7: e654, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30920170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30920170</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30920170[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/mgg3.654" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30920170">Maffezzini et al. (2019)</a> identified compound heterozygous missense mutations in the WARS2 gene: K313M (<a href="#0003">604733.0003</a>) and V278G (<a href="#0010">604733.0010</a>). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both were found at low frequencies in the gnomAD database (1.5 x 10(-4) for K313M and 2.4 x 10(-4) for V278G). Expression of the corresponding mutations in wars2-null yeast resulted in variable growth defects and impaired mitochondrial respiration. Patient fibroblasts showed a reduction in fully aminoacylated tRNA(Trp), but there was not a decrease in mitochondrial respiration. However, patient fibroblasts reprogrammed into neuroepithelial cells confirmed the aminoacylation defect and showed a defect in mitochondrial gene expression, decreased oxygen consumption, and decreased activities of complexes I and IV, suggesting impaired mitochondrial function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30920170" 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>Parkinsonism-Dystonia 3, Childhood-Onset</em></strong></p><p>
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In a 17-year-old boy with childhood-onset parkinsonism-dystonia-3 (PKDYS3; <a href="/entry/619738">619738</a>), <a href="#2" class="mim-tip-reference" title="Burke, E. A., Frucht, S. J., Thompson, K., Wolfe, L. A., Yokoyama, T., Bertoni, M., Huang, Y., Sincan, M., Adams, D. R., Taylor, R. W., Gahl, W. A., Toro, C., Malicdan, M. C. V. <strong>Biallelic mutations in mitochondrial tryptophanyl-tRNA synthetase cause levodopa-responsive infantile-onset parkinsonism.</strong> Clin. Genet. 93: 712-718, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29120065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29120065</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29120065[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1111/cge.13172" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29120065">Burke et al. (2018)</a> identified compound heterozygous missense mutations in the WARS2 gene: W13G (<a href="#0002">604733.0002</a>) and S228W (<a href="#0008">604733.0008</a>). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. W13G was present in the ExAC database with an allelic frequency of 0.0034 and was not predicted to be extremely deleterious, whereas S228W was not present in ExAC. Patient skeletal muscle biopsy showed mild mitochondrial abnormalities, although OXPHOS activity was normal; the authors postulated that mitochondrial dysfunction contributed to nigrostriatal degeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29120065" 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 31-year-old man with PKDYS3, <a href="#3" class="mim-tip-reference" title="Hubers, A., Huppertz, H.-J., Wortmann, S. B., Kassubek, J. <strong>Mutation of the WARS2 gene as the cause of a severe hyperkinetic movement disorder.</strong> Mov. Disord. Clin. Pract. 7: 88-90, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31970218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31970218</a>] [<a href="https://doi.org/10.1002/mdc3.12855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31970218">Hubers et al. (2019)</a> identified compound heterozygous missense mutations in the WARS2 gene: W13G and G50D (<a href="#0009">604733.0009</a>). The mutations, which were found by trio-based exome sequencing, segregated with the disorder in the family. W13G was found 9 times in the homozygous state in the gnomAD database, consistent with it being a hypomorphic allele and only disease-causing when combined with a more deleterious allele. G50D was not present in gnomAD. Functional studies of the variants and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31970218" 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 6 patients from 4 unrelated families with PKDYS3, <a href="#8" class="mim-tip-reference" title="Skorvanek, M., Rektorova, I., Mandemakers, W., Wagner, M., Steinfeld, R., Orec, L., Han, V., Pavelekova, P., Lackova, A., Kulcsarova, K., Ostrozovicova, M., Gdovinova, Z., and 14 others. <strong>WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia.</strong> Parkinsonism Relat. Disord. 94: 54-61, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34890876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34890876</a>] [<a href="https://doi.org/10.1016/j.parkreldis.2021.11.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34890876">Skorvanek et al. (2022)</a> identified compound heterozygous mutations in the WARS2 gene. All patients carried a W13G variant on 1 allele. Two sibs from family 1 had a deletion of exon 2 on the other allele (<a href="#0011">604733.0011</a>). Fibroblasts derived from these patients showed decreased levels of full-length WARS2 protein compared to controls. Two sibs from family 2 carried leu100del (<a href="#0004">604733.0004</a>) on the other allele; functional studies were not performed. The patient from family 3 carried G50D (<a href="#0009">604733.0009</a>) on the other allele; functional studies were not performed. The patient from family 4 carried a c.622G-T transversion, resulting in a glu208-to-ter (E208X; <a href="#0012">604733.0012</a>) substitution on the other allele; functional studies were not performed, but it was predicted to result in premature termination. Overall, the findings indicated that biallelic loss-of-function or hypomorphic mutations in the WARS2 gene lead to mitochondrial dysfunction and disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34890876" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Maffezzini, C., Laine, I., Dallabona, C., Clemente, P., Calvo-Garrido, J., Wibom, R., Naess, K., Barbaro, M., Falk, A., Donnini, C., Freyer, C., Wredenberg, A., Wedell, A. <strong>Mutations in the mitochondrial tryptophanyl-tRNA synthetase cause growth retardation and progressive leukoencephalopathy.</strong> Molec. Genet. Genomic Med. 7: e654, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30920170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30920170</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30920170[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/mgg3.654" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30920170">Maffezzini et al. (2019)</a> found that homozygous loss of wars2 in Drosophila caused larval or pupal lethality associated with a severe reduction in oxygen consumption and respiratory chain enzyme activities, consistent with mitochondrial dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30920170" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 sisters, born of consanguineous Iranian parents (family 2), with mitochondrial neurodevelopmental disorder with abnormal movements and lactic acidosis and without seizures (NEMMLAS; <a href="/entry/617710">617710</a>), <a href="#7" class="mim-tip-reference" title="Musante, L., Puttmann, L., Kahrizi, K., Garshasbi, M., Hu, H., Stehr, H., Lipkowitz, B., Otto, S., Jensen, L. R., Tzschach, A., Jamali, P., Wienker, T., Najmabadi, H., Ropers, H. H., Kuss, A. W. <strong>Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability.</strong> Hum. Mutat. 38: 621-636, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28236339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28236339</a>] [<a href="https://doi.org/10.1002/humu.23205" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28236339">Musante et al. (2017)</a> identified compound heterozygous mutations in the WARS2 gene: a 1-bp deletion (c.325delA, NM_201263.2) in exon 2, resulting in a frameshift and premature termination (Ser109AlafsTer15), and a c.37T-G transversion in exon 1, resulting in a trp13-to-gly (W13G; <a href="/entry/191050#0002">191050.0002</a>) substitution in the N-terminal mitochondrial signal peptide. The mutations, which were found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variants were filtered against the dbSNP (build 138), Exome Variant Server, 1000 Genomes Project, and ExAC databases, as well as several in-house control databases. The c.325delA mutation was predicted to result in nonsense-mediated mRNA decay and a complete loss of function. The W13G variant was found at a low frequency in the ExAC database (0.003383). In vitro functional expression studies in COS-7 and HEK293 cells showed that the W13G mutation resulted in impaired localization of the WARS2 mutant protein to the mitochondria. <a href="#7" class="mim-tip-reference" title="Musante, L., Puttmann, L., Kahrizi, K., Garshasbi, M., Hu, H., Stehr, H., Lipkowitz, B., Otto, S., Jensen, L. R., Tzschach, A., Jamali, P., Wienker, T., Najmabadi, H., Ropers, H. H., Kuss, A. W. <strong>Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability.</strong> Hum. Mutat. 38: 621-636, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28236339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28236339</a>] [<a href="https://doi.org/10.1002/humu.23205" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28236339">Musante et al. (2017)</a> suggested that the W13G variant may be a hypomorphic polymorphism that becomes significant only when paired with a loss-of-function allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28236339" 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>Mitochondrial Neurodevelopmental Disorder with Abnormal Movements and Lactic Acidosis and without Seizures</em></strong></p><p>
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For discussion of the c.37T-G transversion (c.37T-G, NM_201263.2) in the WARS2 gene, resulting in a trp13-to-gly (W13G) substitution, that was found in compound heterozygous state in 2 sisters with mitochondrial neurodevelopmental disorder with abnormal movements and lactic acidosis and without seizures (NEMMLAS; <a href="/entry/617710">617710</a>) by <a href="#7" class="mim-tip-reference" title="Musante, L., Puttmann, L., Kahrizi, K., Garshasbi, M., Hu, H., Stehr, H., Lipkowitz, B., Otto, S., Jensen, L. R., Tzschach, A., Jamali, P., Wienker, T., Najmabadi, H., Ropers, H. H., Kuss, A. W. <strong>Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability.</strong> Hum. Mutat. 38: 621-636, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28236339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28236339</a>] [<a href="https://doi.org/10.1002/humu.23205" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28236339">Musante et al. (2017)</a>, see <a href="#0001">604733.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28236339" 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>Childhood-Onset Parkinsonism-Dystonia 3</em></strong></p><p>
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In a 17-year-old boy with childhood-onset parkinsonism-dystonia-3 (PKDYS3; <a href="/entry/619738">619738</a>), <a href="#2" class="mim-tip-reference" title="Burke, E. A., Frucht, S. J., Thompson, K., Wolfe, L. A., Yokoyama, T., Bertoni, M., Huang, Y., Sincan, M., Adams, D. R., Taylor, R. W., Gahl, W. A., Toro, C., Malicdan, M. C. V. <strong>Biallelic mutations in mitochondrial tryptophanyl-tRNA synthetase cause levodopa-responsive infantile-onset parkinsonism.</strong> Clin. Genet. 93: 712-718, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29120065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29120065</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29120065[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1111/cge.13172" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29120065">Burke et al. (2018)</a> identified compound heterozygous missense mutations in the WARS2 gene: a W13G substitution in exon 1, affecting the mitochondrial localization signal, and a c.683C-G transversion in exon 6, resulting in a ser228-to-trp (S228W; <a href="#0008">604733.0008</a>) substitution in the tryptophan-tRNA ligase domain. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. W13G was present in the ExAC database with an allelic frequency of 0.0034 and was not predicted to be extremely deleterious, whereas S228W was not present in ExAC. Western blot analysis of patient cells showed a marked decrease in steady-state levels of WARS2 compared to controls. Patient skeletal muscle biopsy showed mild mitochondrial abnormalities, although OXPHOS activity was normal; the authors postulated that mitochondrial dysfunction contributed to nigrostriatal degeneration. The patient had onset of levodopa-responsive parkinsonism at about 2 years of age; the disorder was progressive. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29120065" 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 31-year-old man with PKDYS3, <a href="#3" class="mim-tip-reference" title="Hubers, A., Huppertz, H.-J., Wortmann, S. B., Kassubek, J. <strong>Mutation of the WARS2 gene as the cause of a severe hyperkinetic movement disorder.</strong> Mov. Disord. Clin. Pract. 7: 88-90, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31970218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31970218</a>] [<a href="https://doi.org/10.1002/mdc3.12855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31970218">Hubers et al. (2019)</a> identified compound heterozygous missense mutations in the WARS2 gene: W13G and a c.149G-A transition, resulting in a gly50-to-asp (G50D; <a href="#0009">604733.0009</a>) substitution. The mutations, which were found by trio-based exome sequencing, segregated with the disorder in the family. W13G was found 9 times in the homozygous state in the gnomAD database, consistent with it being a hypomorphic allele and only disease-causing when combined with a more deleterious allele. G50D was not present in gnomAD. Functional studies of the variants and studies of patient cells were not performed. The patient developed a severe hyperkinetic movement disorder in the first years of life; he also had cognitive defects and could communicate nonverbally on a basic level. Brain imaging showed cerebellar atrophy. He did not have seizures, which may have explained his long survival. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31970218" 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 6 patients from 4 unrelated families with PKDYS3, <a href="#8" class="mim-tip-reference" title="Skorvanek, M., Rektorova, I., Mandemakers, W., Wagner, M., Steinfeld, R., Orec, L., Han, V., Pavelekova, P., Lackova, A., Kulcsarova, K., Ostrozovicova, M., Gdovinova, Z., and 14 others. <strong>WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia.</strong> Parkinsonism Relat. Disord. 94: 54-61, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34890876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34890876</a>] [<a href="https://doi.org/10.1016/j.parkreldis.2021.11.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34890876">Skorvanek et al. (2022)</a> identified compound heterozygous mutations in the WARS2 gene. All patients carried a W13G variant on 1 allele. Two sibs from family 1 had a deletion of exon 2 on the other allele (<a href="#0011">604733.0011</a>). Fibroblasts derived from these patients showed decreased levels of full-length WARS2 protein compared to controls. Two sibs from family 2 carried leu100del (<a href="#0004">604733.0004</a>) on the other allele; functional studies were not performed. The patient from family 3 carried G50D (<a href="#0009">604733.0009</a>) on the other allele; functional studies were not performed. The patient from family 4 carried a c.622G-T transversion, resulting in a glu208-to-ter (E208X; <a href="#0012">604733.0012</a>) substitution on the other allele; functional studies were not performed, but it was predicted to result in premature termination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34890876" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 NEURODEVELOPMENTAL DISORDER, MITOCHONDRIAL, WITH ABNORMAL MOVEMENTS AND LACTIC ACIDOSIS, WITH OR WITHOUT SEIZURES</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs145867327 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs145867327;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/rs145867327?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=rs145867327" 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=rs145867327" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 24-year-old man with mitochondrial neurodevelopmental disorder with abnormal movements and lactic acidosis, with seizures (NEMMLAS; <a href="/entry/617710">617710</a>), <a href="#10" class="mim-tip-reference" title="Theisen, B. E., Rumyantseva, A., Cohen, J. S., Alcaraz, W. A., Shinde, D. N., Tang, S., Srivastava, S., Pevsner, J., Trifunovic, A., Fatemi, A. <strong>Deficiency of WARS2, encoding mitochondrial tryptophanyl tRNA synthetase, causes severe infantile onset leukoencephalopathy.</strong> Am. J. Med. Genet. 173A: 2505-2510, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28650581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28650581</a>] [<a href="https://doi.org/10.1002/ajmg.a.38339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28650581">Theisen et al. (2017)</a> identified compound heterozygous mutations in the WARS2 gene: a c.938A-T transversion, resulting in a lys313-to-met (K313M) substitution at a conserved residue, and a 3-bp in-frame deletion (c.298_300delCTT; <a href="#0004">604733.0004</a>), resulting in the deletion of leu100 at a conserved residue in the catalytic core domain. The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. The K313M variant was found at a low frequency in the ExAC database (18 of 121,412 alleles, 0.0001483) and the gnomAD database (74 of 282,690 alleles, 2.62 x 10(-4)). However, it was not found in homozygous state. Patient fibroblasts showed decreased de novo synthesis of proteins within the mitochondria, leading to significantly decreased steady-state levels of respiratory chain subunits and lower oxygen consumption rates compared to controls (about 30%). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28650581" 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 boys, born of unrelated Dutch parents (family F2), with NEMMLAS, <a href="#11" class="mim-tip-reference" title="Wortmann, S. B., Timal, S., Venselaar, H., Wintjes, L. T., Kopajtich, R., Feichtinger, R. G., Onnekink, C., Mulmeister, M., Brandt, U., Smeitink, J. A., Veltman, J. A., Sperl, W., and 12 others. <strong>Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy.</strong> Hum. Mutat. 38: 1786-1795, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28905505/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28905505</a>] [<a href="https://doi.org/10.1002/humu.23340" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28905505">Wortmann et al. (2017)</a> identified compound heterozygous mutations in the WARS2 gene: a c.938A-T transversion in exon 6, resulting in a lys313-to-met (K313M) substitution at a highly conserved residue in the anti-codon recognition domain, and a 1-bp deletion in exon 6 (c.797delC; <a href="#0005">604733.0005</a>), resulting in a frameshift and premature termination (Pro266ArgfsTer10). An unrelated patient (I6), born of unrelated Canadian parents (family F5), without seizures was compound heterozygous for K313M and a c.134G-T transversion in exon 2, resulting in a gly45-to-val (G45V; <a href="#0006">604733.0006</a>) substitution at a conserved residue within a small loop that covers the tRNA binding site. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. They were filtered against the dbSNP (build 137) and gnomAD databases. In the gnomAD database, the K313M and c.797delC variants were found at low frequencies (0.0001407 and 4.07 x 10(-5), respectively), and the G45V variant was not listed. Studies of patient cells showed that the K313M mutant protein was sensitive to proteolytic degradation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28905505" 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 sisters, born of unrelated Swedish parents, with NEMMLAS, <a href="#5" class="mim-tip-reference" title="Maffezzini, C., Laine, I., Dallabona, C., Clemente, P., Calvo-Garrido, J., Wibom, R., Naess, K., Barbaro, M., Falk, A., Donnini, C., Freyer, C., Wredenberg, A., Wedell, A. <strong>Mutations in the mitochondrial tryptophanyl-tRNA synthetase cause growth retardation and progressive leukoencephalopathy.</strong> Molec. Genet. Genomic Med. 7: e654, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30920170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30920170</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30920170[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/mgg3.654" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30920170">Maffezzini et al. (2019)</a> identified compound heterozygous missense mutations in the WARS2 gene: K313M and a c.833T-G transversion, resulting in a val278-to-gly (V278G; <a href="#0010">604733.0010</a>) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both were found at low frequencies in the gnomAD database (1.5 x 10(-4) for K313M and 2.4 x 10(-4) for V278G). Expression of the corresponding mutations in wars2-null yeast showed variable growth defects and impaired mitochondrial respiration. Patient fibroblasts showed a reduction in fully aminoacylated tRNA(Trp), but there was not a decrease in mitochondrial respiration. However, patient fibroblasts reprogrammed into neuroepithelial cells confirmed the aminoacylation defect and showed a defect in mitochondrial gene expression, decreased oxygen consumption, and decreased activities of complexes I and IV, suggesting impaired mitochondrial function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30920170" 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 22-year-old Swedish woman with NEMMLAS, <a href="#4" class="mim-tip-reference" title="Ilinca, A., Kafantari, E., Puschmann, A. <strong>A relatively common hypomorphic variant in WARS2 causes monogenic disease.</strong> Parkinsonism Relat. Disord. 94: 129-131, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35074316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35074316</a>] [<a href="https://doi.org/10.1016/j.parkreldis.2022.01.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35074316">Ilinca et al. (2022)</a> identified compound heterozygosity for the K313M and V278G mutations in the WARS2 gene. She had onset of persistent epilepsy in the neonatal period and Levodopa-responsive parkinsonism. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35074316" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 NEURODEVELOPMENTAL DISORDER, MITOCHONDRIAL, WITH ABNORMAL MOVEMENTS AND LACTIC ACIDOSIS, WITH SEIZURES</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs772867219 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs772867219;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/rs772867219?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=rs772867219" 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=rs772867219" 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=RCV000509070 OR RCV000623999 OR RCV001836832" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000509070, RCV000623999, RCV001836832" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000509070...</a>
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<p><strong><em>Mitochondrial Neurodevelopmental Disorder with Abnormal Movements, Lactic Acidosis, and Seizures</em></strong></p><p>
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For discussion of the 3-bp in-frame deletion (c.298_300delCTT) in the WARS2 gene, resulting in the deletion of leu100 (Leu100del), that was found in compound heterozygous state in a patient with mitochondrial neurodevelopmental disorder with abnormal movements, lactic acidosis, and seizures (NEMMLAS; <a href="/entry/617710">617710</a>) by <a href="#10" class="mim-tip-reference" title="Theisen, B. E., Rumyantseva, A., Cohen, J. S., Alcaraz, W. A., Shinde, D. N., Tang, S., Srivastava, S., Pevsner, J., Trifunovic, A., Fatemi, A. <strong>Deficiency of WARS2, encoding mitochondrial tryptophanyl tRNA synthetase, causes severe infantile onset leukoencephalopathy.</strong> Am. J. Med. Genet. 173A: 2505-2510, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28650581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28650581</a>] [<a href="https://doi.org/10.1002/ajmg.a.38339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28650581">Theisen et al. (2017)</a>, see <a href="#0003">604733.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28650581" 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>Childhood-Onset Parkinsonism-Dystonia 3</em></strong></p><p>
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For discussion of the leu100del mutation (c.298_300delCTT, NM_015836.3) in the WARS2 gene that was found in compound heterozygous state in 2 sibs with childhood-onset parkinsonism-dystonia-3 (PKDYS3; <a href="/entry/619738">619738</a>) by <a href="#8" class="mim-tip-reference" title="Skorvanek, M., Rektorova, I., Mandemakers, W., Wagner, M., Steinfeld, R., Orec, L., Han, V., Pavelekova, P., Lackova, A., Kulcsarova, K., Ostrozovicova, M., Gdovinova, Z., and 14 others. <strong>WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia.</strong> Parkinsonism Relat. Disord. 94: 54-61, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34890876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34890876</a>] [<a href="https://doi.org/10.1016/j.parkreldis.2021.11.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34890876">Skorvanek et al. (2022)</a>, see <a href="#0002">604733.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34890876" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 NEURODEVELOPMENTAL DISORDER, MITOCHONDRIAL, WITH ABNORMAL MOVEMENTS AND LACTIC ACIDOSIS, WITH SEIZURES</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs746478253 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs746478253;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/rs746478253?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=rs746478253" 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=rs746478253" 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=RCV000509079 OR RCV000624348 OR RCV001821423 OR RCV003147494" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000509079, RCV000624348, RCV001821423, RCV003147494" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000509079...</a>
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<p>For discussion of the 1-bp deletion in exon 6 (c.797delC, NM_015836.3) of the WARS2 gene, resulting in a frameshift and premature termination (Pro266ArgfsTer10), that was found in compound heterozygous state in a patient with mitochondrial neurodevelopmental disorder with abnormal movements, lactic acidosis, and seizures (NEMMLAS; <a href="/entry/617710">617710</a>) by <a href="#11" class="mim-tip-reference" title="Wortmann, S. B., Timal, S., Venselaar, H., Wintjes, L. T., Kopajtich, R., Feichtinger, R. G., Onnekink, C., Mulmeister, M., Brandt, U., Smeitink, J. A., Veltman, J. A., Sperl, W., and 12 others. <strong>Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy.</strong> Hum. Mutat. 38: 1786-1795, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28905505/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28905505</a>] [<a href="https://doi.org/10.1002/humu.23340" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28905505">Wortmann et al. (2017)</a>, see <a href="#0003">604733.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28905505" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<span class="mim-font">
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<strong>.0006 NEURODEVELOPMENTAL DISORDER, MITOCHONDRIAL, WITH ABNORMAL MOVEMENTS AND LACTIC ACIDOSIS, WITH SEIZURES</strong>
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WARS2, GLY45VAL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1553241795 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1553241795;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=rs1553241795" 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=rs1553241795" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000509069" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000509069" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000509069</a>
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</span>
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<span class="mim-text-font">
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<p>For discussion of the c.134G-T transversion (c.134G-T, NM_015836.3) in exon 2 of the WARS2 gene, resulting in a gly45-to-val (G45V) substitution, that was found in compound heterozygous state in a patient with mitochondrial neurodevelopmental disorder with abnormal movements, lactic acidosis, and seizures (NEMMLAS; <a href="/entry/617710">617710</a>) by <a href="#11" class="mim-tip-reference" title="Wortmann, S. B., Timal, S., Venselaar, H., Wintjes, L. T., Kopajtich, R., Feichtinger, R. G., Onnekink, C., Mulmeister, M., Brandt, U., Smeitink, J. A., Veltman, J. A., Sperl, W., and 12 others. <strong>Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy.</strong> Hum. Mutat. 38: 1786-1795, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28905505/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28905505</a>] [<a href="https://doi.org/10.1002/humu.23340" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28905505">Wortmann et al. (2017)</a>, see <a href="#0003">604733.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28905505" 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 id="0007" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0007 NEURODEVELOPMENTAL DISORDER, MITOCHONDRIAL, WITH ABNORMAL MOVEMENTS AND LACTIC ACIDOSIS, WITH SEIZURES</strong>
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<span class="mim-text-font">
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<div style="float: left;">
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WARS2, VAL178LEU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs912133959 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs912133959;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=rs912133959" 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=rs912133959" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000509074" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000509074" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000509074</a>
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</span>
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<span class="mim-text-font">
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<p>In a patient (I5), born of consanguineous Iraqi parents (family 4), with neurodevelopmental disorder with abnormal movements, lactic acidosis, and seizures (NEMMLAS; <a href="/entry/617710">617710</a>), <a href="#11" class="mim-tip-reference" title="Wortmann, S. B., Timal, S., Venselaar, H., Wintjes, L. T., Kopajtich, R., Feichtinger, R. G., Onnekink, C., Mulmeister, M., Brandt, U., Smeitink, J. A., Veltman, J. A., Sperl, W., and 12 others. <strong>Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy.</strong> Hum. Mutat. 38: 1786-1795, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28905505/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28905505</a>] [<a href="https://doi.org/10.1002/humu.23340" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28905505">Wortmann et al. (2017)</a> identified a homozygous c.532G-C transversion (c.532G-C, NM_015836.3) in exon 5 of the WARS2 gene, resulting in a val178-to-leu (V178L) substitution at a conserved residue. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was filtered against the dbSNP (build 137); it was not found in the gnomAD database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28905505" 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 id="0008" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0008 PARKINSONISM-DYSTONIA 3, CHILDHOOD-ONSET</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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<div style="float: left;">
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WARS2, SER228TRP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1647600390 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1647600390;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=rs1647600390" 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=rs1647600390" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001267721 OR RCV001836978" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001267721, RCV001836978" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001267721...</a>
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</span>
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</div>
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<span class="mim-text-font">
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<p>For discussion of the c.683C-G transversion (c.683C-G, NM_015836.3) in exon 6 of the WARS2 gene, resulting in a ser228-to-trp (S228W) substitution, that was found in compound heterozygous state in a patient with childhood-onset parkinsonism-dystonia-3 (PKDYS3; <a href="/entry/619738">619738</a>) by <a href="#2" class="mim-tip-reference" title="Burke, E. A., Frucht, S. J., Thompson, K., Wolfe, L. A., Yokoyama, T., Bertoni, M., Huang, Y., Sincan, M., Adams, D. R., Taylor, R. W., Gahl, W. A., Toro, C., Malicdan, M. C. V. <strong>Biallelic mutations in mitochondrial tryptophanyl-tRNA synthetase cause levodopa-responsive infantile-onset parkinsonism.</strong> Clin. Genet. 93: 712-718, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29120065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29120065</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29120065[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1111/cge.13172" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29120065">Burke et al. (2018)</a>, see <a href="#0002">604733.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29120065" 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 id="0009" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0009 PARKINSONISM-DYSTONIA 3, CHILDHOOD-ONSET</strong>
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</span>
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</h4>
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WARS2, GLY50ASP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1571323203 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1571323203;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=rs1571323203" 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=rs1571323203" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000995910 OR RCV001836927" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000995910, RCV001836927" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000995910...</a>
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</span>
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<span class="mim-text-font">
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<p>For discussion of the c.149G-A transition (c.149G-A, NM_201263.2) in the WARS2 gene, resulting in a gly50-to-asp (G50D) substitution that was found in compound heterozygous state in a patient with childhood-onset parkinsonism-dystonia-3 (PKDYS3; <a href="/entry/619738">619738</a>) by <a href="#3" class="mim-tip-reference" title="Hubers, A., Huppertz, H.-J., Wortmann, S. B., Kassubek, J. <strong>Mutation of the WARS2 gene as the cause of a severe hyperkinetic movement disorder.</strong> Mov. Disord. Clin. Pract. 7: 88-90, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31970218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31970218</a>] [<a href="https://doi.org/10.1002/mdc3.12855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31970218">Hubers et al. (2019)</a>, see <a href="#0002">604733.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31970218" 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 id="0010" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0010 NEURODEVELOPMENTAL DISORDER, MITOCHONDRIAL, WITH ABNORMAL MOVEMENTS AND LACTIC ACIDOSIS, WITH OR WITHOUT SEIZURES</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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WARS2, VAL278GLY
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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> rs765904496 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs765904496;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/rs765904496?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=rs765904496" 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=rs765904496" 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.833T-G transversion (c.833T-G, NM_015836.3) in the WARS2 gene, resulting in a val278-to-gly (V278G) substitution, that was found in 2 sisters with mitochondrial neurodevelopmental disorder with abnormal movements and lactic acidosis with or without seizures (NEMMLAS; <a href="/entry/617710">617710</a>) by <a href="#5" class="mim-tip-reference" title="Maffezzini, C., Laine, I., Dallabona, C., Clemente, P., Calvo-Garrido, J., Wibom, R., Naess, K., Barbaro, M., Falk, A., Donnini, C., Freyer, C., Wredenberg, A., Wedell, A. <strong>Mutations in the mitochondrial tryptophanyl-tRNA synthetase cause growth retardation and progressive leukoencephalopathy.</strong> Molec. Genet. Genomic Med. 7: e654, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30920170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30920170</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30920170[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/mgg3.654" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30920170">Maffezzini et al. (2019)</a>, see <a href="#0003">604733.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30920170" 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="#4" class="mim-tip-reference" title="Ilinca, A., Kafantari, E., Puschmann, A. <strong>A relatively common hypomorphic variant in WARS2 causes monogenic disease.</strong> Parkinsonism Relat. Disord. 94: 129-131, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35074316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35074316</a>] [<a href="https://doi.org/10.1016/j.parkreldis.2022.01.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35074316">Ilinca et al. (2022)</a> found compound heterozygosity for the V278G and K313M (<a href="#0003">604733.0003</a>) mutations in a 22-year-old Swedish woman with NEMMLAS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35074316" 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=RCV001837433" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001837433" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001837433</a>
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<p>For discussion of the exon 2 deletion in the WARS2 gene, resulting in deletion of 86 amino acids (Lys31_Gln116del), that was found in compound heterozygous state in 2 sibs (family 1) with childhood-onset parkinsonism-dystonia-3 (PKDYS3; <a href="/entry/619738">619738</a>) by <a href="#8" class="mim-tip-reference" title="Skorvanek, M., Rektorova, I., Mandemakers, W., Wagner, M., Steinfeld, R., Orec, L., Han, V., Pavelekova, P., Lackova, A., Kulcsarova, K., Ostrozovicova, M., Gdovinova, Z., and 14 others. <strong>WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia.</strong> Parkinsonism Relat. Disord. 94: 54-61, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34890876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34890876</a>] [<a href="https://doi.org/10.1016/j.parkreldis.2021.11.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34890876">Skorvanek et al. (2022)</a>, see <a href="#0002">604733.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34890876" 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> rs137890886 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137890886;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/rs137890886?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=rs137890886" 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=rs137890886" 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=RCV001254139 OR RCV001836976" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001254139, RCV001836976" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001254139...</a>
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<p>For discussion of the c.622G-T transversion (c.622G-T, NM_015836.3) in the WARS2 gene, resulting in a glu208-to-ter (E208X) substitution, that was found in compound heterozygous state in a patient (family 4) with childhood-onset parkinsonism-dystonia-3 (PKDYS3; <a href="/entry/619738">619738</a>) by <a href="#8" class="mim-tip-reference" title="Skorvanek, M., Rektorova, I., Mandemakers, W., Wagner, M., Steinfeld, R., Orec, L., Han, V., Pavelekova, P., Lackova, A., Kulcsarova, K., Ostrozovicova, M., Gdovinova, Z., and 14 others. <strong>WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia.</strong> Parkinsonism Relat. Disord. 94: 54-61, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34890876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34890876</a>] [<a href="https://doi.org/10.1016/j.parkreldis.2021.11.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34890876">Skorvanek et al. (2022)</a>, see <a href="#0002">604733.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34890876" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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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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Burke, E. A., Frucht, S. J., Thompson, K., Wolfe, L. A., Yokoyama, T., Bertoni, M., Huang, Y., Sincan, M., Adams, D. R., Taylor, R. W., Gahl, W. A., Toro, C., Malicdan, M. C. V.
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<strong>Biallelic mutations in mitochondrial tryptophanyl-tRNA synthetase cause levodopa-responsive infantile-onset parkinsonism.</strong>
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Clin. Genet. 93: 712-718, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29120065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29120065</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29120065[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=29120065" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/cge.13172" target="_blank">Full Text</a>]
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Hubers, A., Huppertz, H.-J., Wortmann, S. B., Kassubek, J.
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<strong>Mutation of the WARS2 gene as the cause of a severe hyperkinetic movement disorder.</strong>
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Mov. Disord. Clin. Pract. 7: 88-90, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31970218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31970218</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31970218" 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/mdc3.12855" target="_blank">Full Text</a>]
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Ilinca, A., Kafantari, E., Puschmann, A.
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<strong>A relatively common hypomorphic variant in WARS2 causes monogenic disease.</strong>
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Parkinsonism Relat. Disord. 94: 129-131, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35074316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35074316</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35074316" 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.parkreldis.2022.01.012" target="_blank">Full Text</a>]
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Maffezzini, C., Laine, I., Dallabona, C., Clemente, P., Calvo-Garrido, J., Wibom, R., Naess, K., Barbaro, M., Falk, A., Donnini, C., Freyer, C., Wredenberg, A., Wedell, A.
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<strong>Mutations in the mitochondrial tryptophanyl-tRNA synthetase cause growth retardation and progressive leukoencephalopathy.</strong>
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Molec. Genet. Genomic Med. 7: e654, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30920170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30920170</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30920170[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=30920170" 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/mgg3.654" target="_blank">Full Text</a>]
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Martinez-Dominguez, M. T., Justesen, J., Kruse, T. A., Hansen, L. L.
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<strong>Assignment of the human mitochondrial tryptophanyl-tRNA synthetase (WARS2) to 1p13.3-p13.1 by radiation hybrid mapping.</strong>
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Cytogenet. Cell Genet. 83: 249-250, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10072595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10072595</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10072595" 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/10.1159/000015196" target="_blank">Full Text</a>]
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Musante, L., Puttmann, L., Kahrizi, K., Garshasbi, M., Hu, H., Stehr, H., Lipkowitz, B., Otto, S., Jensen, L. R., Tzschach, A., Jamali, P., Wienker, T., Najmabadi, H., Ropers, H. H., Kuss, A. W.
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|
<strong>Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability.</strong>
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Hum. Mutat. 38: 621-636, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28236339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28236339</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28236339" 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.23205" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="8" class="mim-anchor"></a>
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<a id="Skorvanek2022" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Skorvanek, M., Rektorova, I., Mandemakers, W., Wagner, M., Steinfeld, R., Orec, L., Han, V., Pavelekova, P., Lackova, A., Kulcsarova, K., Ostrozovicova, M., Gdovinova, Z., and 14 others.
|
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<strong>WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia.</strong>
|
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Parkinsonism Relat. Disord. 94: 54-61, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34890876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34890876</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34890876" 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.parkreldis.2021.11.030" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="9" class="mim-anchor"></a>
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<a id="Stumpf2022" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Stumpf, A. M.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 02/17/2022.
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</p>
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</div>
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</li>
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<li>
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<a id="10" class="mim-anchor"></a>
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<a id="Theisen2017" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Theisen, B. E., Rumyantseva, A., Cohen, J. S., Alcaraz, W. A., Shinde, D. N., Tang, S., Srivastava, S., Pevsner, J., Trifunovic, A., Fatemi, A.
|
|
<strong>Deficiency of WARS2, encoding mitochondrial tryptophanyl tRNA synthetase, causes severe infantile onset leukoencephalopathy.</strong>
|
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Am. J. Med. Genet. 173A: 2505-2510, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28650581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28650581</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28650581" 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.38339" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="11" class="mim-anchor"></a>
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<a id="Wortmann2017" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wortmann, S. B., Timal, S., Venselaar, H., Wintjes, L. T., Kopajtich, R., Feichtinger, R. G., Onnekink, C., Mulmeister, M., Brandt, U., Smeitink, J. A., Veltman, J. A., Sperl, W., and 12 others.
|
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<strong>Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy.</strong>
|
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Hum. Mutat. 38: 1786-1795, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28905505/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28905505</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28905505" 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.23340" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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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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Anne M. Stumpf - updated : 02/17/2022
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 02/11/2022<br>Cassandra L. Kniffin - updated : 10/09/2017<br>Patricia A. Hartz - updated : 5/21/2009
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patti M. Sherman : 3/23/2000
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 02/18/2022
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 02/17/2022<br>ckniffin : 02/11/2022<br>carol : 11/13/2017<br>carol : 10/10/2017<br>ckniffin : 10/09/2017<br>carol : 07/20/2016<br>mgross : 05/26/2009<br>terry : 5/21/2009<br>alopez : 8/1/2007<br>mcapotos : 4/7/2000<br>psherman : 3/23/2000
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 604733
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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TRYPTOPHANYL-tRNA SYNTHETASE 2; WARS2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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TRYPTOPHANYL-tRNA SYNTHETASE, MITOCHONDRIAL<br />
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MITOCHONDRIAL TRPRS
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: WARS2</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 1260128008;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 1p12
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Genomic coordinates <span class="small">(GRCh38)</span> : 1:119,031,216-119,140,672 </span>
|
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</em>
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</strong>
|
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
|
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Inheritance
|
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</th>
|
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<th>
|
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="2">
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<span class="mim-font">
|
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1p12
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures
|
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</span>
|
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</td>
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<td>
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<span class="mim-font">
|
|
617710
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
Autosomal recessive
|
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</span>
|
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</td>
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<td>
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<span class="mim-font">
|
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3
|
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
|
|
Parkinsonism-dystonia 3, childhood-onset
|
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</span>
|
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</td>
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<td>
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<span class="mim-font">
|
|
619738
|
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</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
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</h4>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
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<p>Tryptophanyl-tRNA synthetases are essential enzymes that catalyze the aminoacylation of tRNA(trp) with tryptophan. Two forms of tryptophanyl-tRNA synthetase exist, a cytoplasmic form, named WARS (191050), and a mitochondrial form, named WARS2 (Martinez-Dominguez et al., 1998). </p>
|
|
</span>
|
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<div>
|
|
<br />
|
|
</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
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</h4>
|
|
</div>
|
|
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<span class="mim-text-font">
|
|
<p>By homology searching of an EST database, Martinez-Dominguez et al. (1998) identified a WARS2 EST. The deduced WARS2 protein contains a signal peptide for mitochondrial import. WARS2 is highly homologous to bacterial tryptophanyl-tRNA synthetases. </p><p>By searching databases for aminoacyl-tRNA synthetases containing a mitochondrial targeting sequence, Bonnefond et al. (2005) identified WARS2, which they called mitochondrial TRPRS. The deduced 360-amino acid protein has an N-terminal mitochondrial targeting signal that is cleaved after residue 18. WARS2 has characteristics of a class I aminoacyl-tRNA synthetase, including a classical Rossmann fold. </p><p>Musante et al. (2017) found expression of the WARS2 gene in multiple brain regions. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
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</h4>
|
|
</div>
|
|
|
|
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|
|
<span class="mim-text-font">
|
|
<p>Bonnefond et al. (2005) determined that the WARS2 gene contains 6 exons and spans 109 kb. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
|
<span class="mim-text-font">
|
|
<p>By analysis of a radiation hybrid mapping panel, Martinez-Dominguez et al. (1998) mapped the WARS2 gene to chromosome 1p13.3-p13.1, between markers D1S453 and D1S514. </p><p>Stumpf (2022) mapped the WARS2 gene to chromosome 1p12 based on an alignment of the WARS2 sequence (GenBank AK313740) with the genomic sequence (GRCh38).</p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
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|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Mitochondrial Neurodevelopmental Disorder with Abnormal Movements and Lactic Acidosis with or without Seizures</em></strong></p><p>
|
|
In 2 sisters, born of consanguineous Iranian parents (family 2), with mitochondrial neurodevelopmental disorder with abnormal movements and lactic acidosis with or without seizures (NEMMLAS; 617710), Musante et al. (2017) identified compound heterozygous mutations in the WARS2 gene (c.325delC, 604733.0001 and W13G, 604733.0002). The mutations, which were found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies showed that the W13G mutation resulted in impaired localization of the WARS2 mutant protein to the mitochondria. Musante et al. (2017) suggested that the W13G variant may be a hypomorphic polymorphism that becomes significant only when paired with a loss-of-function allele. Of note, overexpression of wildtype WARS2 resulted in decreased SDHA (600857) compared to cells overexpressing the mutant protein; SDHA is part of the mitochondrial respiratory chain. </p><p>In a 24-year-old man with NEMMLAS, Theisen et al. (2017) identified compound heterozygous mutations in the WARS2 gene (K313M, 604733.0003 and c.298_300delCTT, 604733.0004). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Patient fibroblasts showed decreased de novo synthesis of proteins within the mitochondria, leading to significantly decreased steady-state levels of respiratory chain subunits and lower oxygen consumption rates compared to controls (about 30%). </p><p>In 6 patients from 5 unrelated families with NEMMLAS, Wortmann et al. (2017) identified homozygous or compound heterozygous mutations in the WARS2 gene (see, e.g., 604733.0003; 604733.0005-604733.0007). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. There were 6 missense mutations, 1 frameshift, and 1 insertion/deletion. Cells derived from several unrelated patients showed decreased or absent WARS2 protein levels compared to controls. In addition, cells derived from 2 sibs showed a clear decrease in charged mt-tRNA(Trp), while total mt-tRNA(Trp) levels appeared normal. These findings suggested that the defect in WARS2 causes improper aminoacylation of tRNA(Trp), leading to abnormalities in mitochondrial oxidative phosphorylation (OXPHOS) protein synthesis. However, OXPHOS activities in most patient cells were normal, with the exception of 1 severely affected individual and mild changes in some tissues of 2 other patients. Wortmann et al. (2017) postulated that the OXPHOS defect may be apparent in the central nervous system, but such tissue was not available for study. </p><p>In 2 sisters, born of unrelated Swedish parents, with NEMMLAS, Maffezzini et al. (2019) identified compound heterozygous missense mutations in the WARS2 gene: K313M (604733.0003) and V278G (604733.0010). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both were found at low frequencies in the gnomAD database (1.5 x 10(-4) for K313M and 2.4 x 10(-4) for V278G). Expression of the corresponding mutations in wars2-null yeast resulted in variable growth defects and impaired mitochondrial respiration. Patient fibroblasts showed a reduction in fully aminoacylated tRNA(Trp), but there was not a decrease in mitochondrial respiration. However, patient fibroblasts reprogrammed into neuroepithelial cells confirmed the aminoacylation defect and showed a defect in mitochondrial gene expression, decreased oxygen consumption, and decreased activities of complexes I and IV, suggesting impaired mitochondrial function. </p><p><strong><em>Parkinsonism-Dystonia 3, Childhood-Onset</em></strong></p><p>
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In a 17-year-old boy with childhood-onset parkinsonism-dystonia-3 (PKDYS3; 619738), Burke et al. (2018) identified compound heterozygous missense mutations in the WARS2 gene: W13G (604733.0002) and S228W (604733.0008). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. W13G was present in the ExAC database with an allelic frequency of 0.0034 and was not predicted to be extremely deleterious, whereas S228W was not present in ExAC. Patient skeletal muscle biopsy showed mild mitochondrial abnormalities, although OXPHOS activity was normal; the authors postulated that mitochondrial dysfunction contributed to nigrostriatal degeneration. </p><p>In a 31-year-old man with PKDYS3, Hubers et al. (2019) identified compound heterozygous missense mutations in the WARS2 gene: W13G and G50D (604733.0009). The mutations, which were found by trio-based exome sequencing, segregated with the disorder in the family. W13G was found 9 times in the homozygous state in the gnomAD database, consistent with it being a hypomorphic allele and only disease-causing when combined with a more deleterious allele. G50D was not present in gnomAD. Functional studies of the variants and studies of patient cells were not performed. </p><p>In 6 patients from 4 unrelated families with PKDYS3, Skorvanek et al. (2022) identified compound heterozygous mutations in the WARS2 gene. All patients carried a W13G variant on 1 allele. Two sibs from family 1 had a deletion of exon 2 on the other allele (604733.0011). Fibroblasts derived from these patients showed decreased levels of full-length WARS2 protein compared to controls. Two sibs from family 2 carried leu100del (604733.0004) on the other allele; functional studies were not performed. The patient from family 3 carried G50D (604733.0009) on the other allele; functional studies were not performed. The patient from family 4 carried a c.622G-T transversion, resulting in a glu208-to-ter (E208X; 604733.0012) substitution on the other allele; functional studies were not performed, but it was predicted to result in premature termination. Overall, the findings indicated that biallelic loss-of-function or hypomorphic mutations in the WARS2 gene lead to mitochondrial dysfunction and disease. </p>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</h4>
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<p>Maffezzini et al. (2019) found that homozygous loss of wars2 in Drosophila caused larval or pupal lethality associated with a severe reduction in oxygen consumption and respiratory chain enzyme activities, consistent with mitochondrial dysfunction. </p>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>12 Selected Examples):</strong>
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</span>
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</h4>
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<p />
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<h4>
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<span class="mim-font">
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<strong>.0001 NEURODEVELOPMENTAL DISORDER, MITOCHONDRIAL, WITH ABNORMAL MOVEMENTS AND LACTIC ACIDOSIS, WITHOUT SEIZURES</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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WARS2, 1-BP DEL, 325A
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<br />
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SNP: rs1253426801,
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gnomAD: rs1253426801,
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ClinVar: RCV000509073, RCV002527378
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</span>
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<span class="mim-text-font">
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<p>In 2 sisters, born of consanguineous Iranian parents (family 2), with mitochondrial neurodevelopmental disorder with abnormal movements and lactic acidosis and without seizures (NEMMLAS; 617710), Musante et al. (2017) identified compound heterozygous mutations in the WARS2 gene: a 1-bp deletion (c.325delA, NM_201263.2) in exon 2, resulting in a frameshift and premature termination (Ser109AlafsTer15), and a c.37T-G transversion in exon 1, resulting in a trp13-to-gly (W13G; 191050.0002) substitution in the N-terminal mitochondrial signal peptide. The mutations, which were found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variants were filtered against the dbSNP (build 138), Exome Variant Server, 1000 Genomes Project, and ExAC databases, as well as several in-house control databases. The c.325delA mutation was predicted to result in nonsense-mediated mRNA decay and a complete loss of function. The W13G variant was found at a low frequency in the ExAC database (0.003383). In vitro functional expression studies in COS-7 and HEK293 cells showed that the W13G mutation resulted in impaired localization of the WARS2 mutant protein to the mitochondria. Musante et al. (2017) suggested that the W13G variant may be a hypomorphic polymorphism that becomes significant only when paired with a loss-of-function allele. </p>
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</span>
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<br />
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 NEURODEVELOPMENTAL DISORDER, MITOCHONDRIAL, WITH ABNORMAL MOVEMENTS AND LACTIC ACIDOSIS, WITHOUT SEIZURES</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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PARKINSONISM-DYSTONIA 3, CHILDHOOD-ONSET, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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WARS2, TRP13GLY
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<br />
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SNP: rs139548132,
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gnomAD: rs139548132,
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ClinVar: RCV000509078, RCV000894409, RCV001836831, RCV002524935, RCV003235260, RCV004017657
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p />
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<p><strong><em>Mitochondrial Neurodevelopmental Disorder with Abnormal Movements and Lactic Acidosis and without Seizures</em></strong></p><p>
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For discussion of the c.37T-G transversion (c.37T-G, NM_201263.2) in the WARS2 gene, resulting in a trp13-to-gly (W13G) substitution, that was found in compound heterozygous state in 2 sisters with mitochondrial neurodevelopmental disorder with abnormal movements and lactic acidosis and without seizures (NEMMLAS; 617710) by Musante et al. (2017), see 604733.0001. </p><p><strong><em>Childhood-Onset Parkinsonism-Dystonia 3</em></strong></p><p>
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In a 17-year-old boy with childhood-onset parkinsonism-dystonia-3 (PKDYS3; 619738), Burke et al. (2018) identified compound heterozygous missense mutations in the WARS2 gene: a W13G substitution in exon 1, affecting the mitochondrial localization signal, and a c.683C-G transversion in exon 6, resulting in a ser228-to-trp (S228W; 604733.0008) substitution in the tryptophan-tRNA ligase domain. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. W13G was present in the ExAC database with an allelic frequency of 0.0034 and was not predicted to be extremely deleterious, whereas S228W was not present in ExAC. Western blot analysis of patient cells showed a marked decrease in steady-state levels of WARS2 compared to controls. Patient skeletal muscle biopsy showed mild mitochondrial abnormalities, although OXPHOS activity was normal; the authors postulated that mitochondrial dysfunction contributed to nigrostriatal degeneration. The patient had onset of levodopa-responsive parkinsonism at about 2 years of age; the disorder was progressive. </p><p>In a 31-year-old man with PKDYS3, Hubers et al. (2019) identified compound heterozygous missense mutations in the WARS2 gene: W13G and a c.149G-A transition, resulting in a gly50-to-asp (G50D; 604733.0009) substitution. The mutations, which were found by trio-based exome sequencing, segregated with the disorder in the family. W13G was found 9 times in the homozygous state in the gnomAD database, consistent with it being a hypomorphic allele and only disease-causing when combined with a more deleterious allele. G50D was not present in gnomAD. Functional studies of the variants and studies of patient cells were not performed. The patient developed a severe hyperkinetic movement disorder in the first years of life; he also had cognitive defects and could communicate nonverbally on a basic level. Brain imaging showed cerebellar atrophy. He did not have seizures, which may have explained his long survival. </p><p>In 6 patients from 4 unrelated families with PKDYS3, Skorvanek et al. (2022) identified compound heterozygous mutations in the WARS2 gene. All patients carried a W13G variant on 1 allele. Two sibs from family 1 had a deletion of exon 2 on the other allele (604733.0011). Fibroblasts derived from these patients showed decreased levels of full-length WARS2 protein compared to controls. Two sibs from family 2 carried leu100del (604733.0004) on the other allele; functional studies were not performed. The patient from family 3 carried G50D (604733.0009) on the other allele; functional studies were not performed. The patient from family 4 carried a c.622G-T transversion, resulting in a glu208-to-ter (E208X; 604733.0012) substitution on the other allele; functional studies were not performed, but it was predicted to result in premature termination. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 NEURODEVELOPMENTAL DISORDER, MITOCHONDRIAL, WITH ABNORMAL MOVEMENTS AND LACTIC ACIDOSIS, WITH OR WITHOUT SEIZURES</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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WARS2, LYS313MET
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<br />
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SNP: rs145867327,
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gnomAD: rs145867327,
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ClinVar: RCV000509075, RCV000622962, RCV001726205, RCV003323579
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 24-year-old man with mitochondrial neurodevelopmental disorder with abnormal movements and lactic acidosis, with seizures (NEMMLAS; 617710), Theisen et al. (2017) identified compound heterozygous mutations in the WARS2 gene: a c.938A-T transversion, resulting in a lys313-to-met (K313M) substitution at a conserved residue, and a 3-bp in-frame deletion (c.298_300delCTT; 604733.0004), resulting in the deletion of leu100 at a conserved residue in the catalytic core domain. The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. The K313M variant was found at a low frequency in the ExAC database (18 of 121,412 alleles, 0.0001483) and the gnomAD database (74 of 282,690 alleles, 2.62 x 10(-4)). However, it was not found in homozygous state. Patient fibroblasts showed decreased de novo synthesis of proteins within the mitochondria, leading to significantly decreased steady-state levels of respiratory chain subunits and lower oxygen consumption rates compared to controls (about 30%). </p><p>In 2 boys, born of unrelated Dutch parents (family F2), with NEMMLAS, Wortmann et al. (2017) identified compound heterozygous mutations in the WARS2 gene: a c.938A-T transversion in exon 6, resulting in a lys313-to-met (K313M) substitution at a highly conserved residue in the anti-codon recognition domain, and a 1-bp deletion in exon 6 (c.797delC; 604733.0005), resulting in a frameshift and premature termination (Pro266ArgfsTer10). An unrelated patient (I6), born of unrelated Canadian parents (family F5), without seizures was compound heterozygous for K313M and a c.134G-T transversion in exon 2, resulting in a gly45-to-val (G45V; 604733.0006) substitution at a conserved residue within a small loop that covers the tRNA binding site. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. They were filtered against the dbSNP (build 137) and gnomAD databases. In the gnomAD database, the K313M and c.797delC variants were found at low frequencies (0.0001407 and 4.07 x 10(-5), respectively), and the G45V variant was not listed. Studies of patient cells showed that the K313M mutant protein was sensitive to proteolytic degradation. </p><p>In 2 sisters, born of unrelated Swedish parents, with NEMMLAS, Maffezzini et al. (2019) identified compound heterozygous missense mutations in the WARS2 gene: K313M and a c.833T-G transversion, resulting in a val278-to-gly (V278G; 604733.0010) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both were found at low frequencies in the gnomAD database (1.5 x 10(-4) for K313M and 2.4 x 10(-4) for V278G). Expression of the corresponding mutations in wars2-null yeast showed variable growth defects and impaired mitochondrial respiration. Patient fibroblasts showed a reduction in fully aminoacylated tRNA(Trp), but there was not a decrease in mitochondrial respiration. However, patient fibroblasts reprogrammed into neuroepithelial cells confirmed the aminoacylation defect and showed a defect in mitochondrial gene expression, decreased oxygen consumption, and decreased activities of complexes I and IV, suggesting impaired mitochondrial function. </p><p>In a 22-year-old Swedish woman with NEMMLAS, Ilinca et al. (2022) identified compound heterozygosity for the K313M and V278G mutations in the WARS2 gene. She had onset of persistent epilepsy in the neonatal period and Levodopa-responsive parkinsonism. Functional studies of the variant and studies of patient cells were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0004 NEURODEVELOPMENTAL DISORDER, MITOCHONDRIAL, WITH ABNORMAL MOVEMENTS AND LACTIC ACIDOSIS, WITH SEIZURES</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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PARKINSONISM-DYSTONIA 3, CHILDHOOD-ONSET, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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WARS2, 3-BP DEL, 298CTT
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<br />
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SNP: rs772867219,
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gnomAD: rs772867219,
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ClinVar: RCV000509070, RCV000623999, RCV001836832
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p />
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<p><strong><em>Mitochondrial Neurodevelopmental Disorder with Abnormal Movements, Lactic Acidosis, and Seizures</em></strong></p><p>
|
|
For discussion of the 3-bp in-frame deletion (c.298_300delCTT) in the WARS2 gene, resulting in the deletion of leu100 (Leu100del), that was found in compound heterozygous state in a patient with mitochondrial neurodevelopmental disorder with abnormal movements, lactic acidosis, and seizures (NEMMLAS; 617710) by Theisen et al. (2017), see 604733.0003. </p><p><strong><em>Childhood-Onset Parkinsonism-Dystonia 3</em></strong></p><p>
|
|
For discussion of the leu100del mutation (c.298_300delCTT, NM_015836.3) in the WARS2 gene that was found in compound heterozygous state in 2 sibs with childhood-onset parkinsonism-dystonia-3 (PKDYS3; 619738) by Skorvanek et al. (2022), see 604733.0002. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 NEURODEVELOPMENTAL DISORDER, MITOCHONDRIAL, WITH ABNORMAL MOVEMENTS AND LACTIC ACIDOSIS, WITH SEIZURES</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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WARS2, 1-BP DEL, 797C
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<br />
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SNP: rs746478253,
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gnomAD: rs746478253,
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ClinVar: RCV000509079, RCV000624348, RCV001821423, RCV003147494
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the 1-bp deletion in exon 6 (c.797delC, NM_015836.3) of the WARS2 gene, resulting in a frameshift and premature termination (Pro266ArgfsTer10), that was found in compound heterozygous state in a patient with mitochondrial neurodevelopmental disorder with abnormal movements, lactic acidosis, and seizures (NEMMLAS; 617710) by Wortmann et al. (2017), see 604733.0003. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 NEURODEVELOPMENTAL DISORDER, MITOCHONDRIAL, WITH ABNORMAL MOVEMENTS AND LACTIC ACIDOSIS, WITH SEIZURES</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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WARS2, GLY45VAL
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<br />
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SNP: rs1553241795,
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ClinVar: RCV000509069
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the c.134G-T transversion (c.134G-T, NM_015836.3) in exon 2 of the WARS2 gene, resulting in a gly45-to-val (G45V) substitution, that was found in compound heterozygous state in a patient with mitochondrial neurodevelopmental disorder with abnormal movements, lactic acidosis, and seizures (NEMMLAS; 617710) by Wortmann et al. (2017), see 604733.0003. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 NEURODEVELOPMENTAL DISORDER, MITOCHONDRIAL, WITH ABNORMAL MOVEMENTS AND LACTIC ACIDOSIS, WITH SEIZURES</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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WARS2, VAL178LEU
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<br />
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SNP: rs912133959,
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ClinVar: RCV000509074
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</span>
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<span class="mim-text-font">
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<p>In a patient (I5), born of consanguineous Iraqi parents (family 4), with neurodevelopmental disorder with abnormal movements, lactic acidosis, and seizures (NEMMLAS; 617710), Wortmann et al. (2017) identified a homozygous c.532G-C transversion (c.532G-C, NM_015836.3) in exon 5 of the WARS2 gene, resulting in a val178-to-leu (V178L) substitution at a conserved residue. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was filtered against the dbSNP (build 137); it was not found in the gnomAD database. </p>
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</span>
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</div>
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<div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0008 PARKINSONISM-DYSTONIA 3, CHILDHOOD-ONSET</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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WARS2, SER228TRP
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<br />
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SNP: rs1647600390,
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ClinVar: RCV001267721, RCV001836978
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the c.683C-G transversion (c.683C-G, NM_015836.3) in exon 6 of the WARS2 gene, resulting in a ser228-to-trp (S228W) substitution, that was found in compound heterozygous state in a patient with childhood-onset parkinsonism-dystonia-3 (PKDYS3; 619738) by Burke et al. (2018), see 604733.0002. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0009 PARKINSONISM-DYSTONIA 3, CHILDHOOD-ONSET</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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WARS2, GLY50ASP
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<br />
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SNP: rs1571323203,
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ClinVar: RCV000995910, RCV001836927
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the c.149G-A transition (c.149G-A, NM_201263.2) in the WARS2 gene, resulting in a gly50-to-asp (G50D) substitution that was found in compound heterozygous state in a patient with childhood-onset parkinsonism-dystonia-3 (PKDYS3; 619738) by Hubers et al. (2019), see 604733.0002. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0010 NEURODEVELOPMENTAL DISORDER, MITOCHONDRIAL, WITH ABNORMAL MOVEMENTS AND LACTIC ACIDOSIS, WITH OR WITHOUT SEIZURES</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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WARS2, VAL278GLY
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<br />
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SNP: rs765904496,
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gnomAD: rs765904496,
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ClinVar: RCV001837432, RCV002285505
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the c.833T-G transversion (c.833T-G, NM_015836.3) in the WARS2 gene, resulting in a val278-to-gly (V278G) substitution, that was found in 2 sisters with mitochondrial neurodevelopmental disorder with abnormal movements and lactic acidosis with or without seizures (NEMMLAS; 617710) by Maffezzini et al. (2019), see 604733.0003. </p><p>Ilinca et al. (2022) found compound heterozygosity for the V278G and K313M (604733.0003) mutations in a 22-year-old Swedish woman with NEMMLAS. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0011 PARKINSONISM-DYSTONIA 3, CHILDHOOD-ONSET</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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WARS2, EX2 DEL
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<br />
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ClinVar: RCV001837433
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the exon 2 deletion in the WARS2 gene, resulting in deletion of 86 amino acids (Lys31_Gln116del), that was found in compound heterozygous state in 2 sibs (family 1) with childhood-onset parkinsonism-dystonia-3 (PKDYS3; 619738) by Skorvanek et al. (2022), see 604733.0002. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 PARKINSONISM-DYSTONIA 3, CHILDHOOD-ONSET</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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WARS2, GLU208TER
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<br />
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SNP: rs137890886,
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gnomAD: rs137890886,
|
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|
|
ClinVar: RCV001254139, RCV001836976
|
|
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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.622G-T transversion (c.622G-T, NM_015836.3) in the WARS2 gene, resulting in a glu208-to-ter (E208X) substitution, that was found in compound heterozygous state in a patient (family 4) with childhood-onset parkinsonism-dystonia-3 (PKDYS3; 619738) by Skorvanek et al. (2022), see 604733.0002. </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>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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<div>
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<ol>
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<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.
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|
[PubMed: 15779907]
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[Full Text: https://doi.org/10.1021/bi047527z]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Burke, E. A., Frucht, S. J., Thompson, K., Wolfe, L. A., Yokoyama, T., Bertoni, M., Huang, Y., Sincan, M., Adams, D. R., Taylor, R. W., Gahl, W. A., Toro, C., Malicdan, M. C. V.
|
|
<strong>Biallelic mutations in mitochondrial tryptophanyl-tRNA synthetase cause levodopa-responsive infantile-onset parkinsonism.</strong>
|
|
Clin. Genet. 93: 712-718, 2018.
|
|
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|
|
[PubMed: 29120065]
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[Full Text: https://doi.org/10.1111/cge.13172]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Hubers, A., Huppertz, H.-J., Wortmann, S. B., Kassubek, J.
|
|
<strong>Mutation of the WARS2 gene as the cause of a severe hyperkinetic movement disorder.</strong>
|
|
Mov. Disord. Clin. Pract. 7: 88-90, 2019.
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[PubMed: 31970218]
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[Full Text: https://doi.org/10.1002/mdc3.12855]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Ilinca, A., Kafantari, E., Puschmann, A.
|
|
<strong>A relatively common hypomorphic variant in WARS2 causes monogenic disease.</strong>
|
|
Parkinsonism Relat. Disord. 94: 129-131, 2022.
|
|
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|
|
[PubMed: 35074316]
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|
[Full Text: https://doi.org/10.1016/j.parkreldis.2022.01.012]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Maffezzini, C., Laine, I., Dallabona, C., Clemente, P., Calvo-Garrido, J., Wibom, R., Naess, K., Barbaro, M., Falk, A., Donnini, C., Freyer, C., Wredenberg, A., Wedell, A.
|
|
<strong>Mutations in the mitochondrial tryptophanyl-tRNA synthetase cause growth retardation and progressive leukoencephalopathy.</strong>
|
|
Molec. Genet. Genomic Med. 7: e654, 2019.
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|
|
[PubMed: 30920170]
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[Full Text: https://doi.org/10.1002/mgg3.654]
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</p>
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</li>
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<li>
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|
<p class="mim-text-font">
|
|
Martinez-Dominguez, M. T., Justesen, J., Kruse, T. A., Hansen, L. L.
|
|
<strong>Assignment of the human mitochondrial tryptophanyl-tRNA synthetase (WARS2) to 1p13.3-p13.1 by radiation hybrid mapping.</strong>
|
|
Cytogenet. Cell Genet. 83: 249-250, 1998.
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|
|
[PubMed: 10072595]
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[Full Text: https://doi.org/10.1159/000015196]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Musante, L., Puttmann, L., Kahrizi, K., Garshasbi, M., Hu, H., Stehr, H., Lipkowitz, B., Otto, S., Jensen, L. R., Tzschach, A., Jamali, P., Wienker, T., Najmabadi, H., Ropers, H. H., Kuss, A. W.
|
|
<strong>Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability.</strong>
|
|
Hum. Mutat. 38: 621-636, 2017.
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|
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|
|
[PubMed: 28236339]
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[Full Text: https://doi.org/10.1002/humu.23205]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Skorvanek, M., Rektorova, I., Mandemakers, W., Wagner, M., Steinfeld, R., Orec, L., Han, V., Pavelekova, P., Lackova, A., Kulcsarova, K., Ostrozovicova, M., Gdovinova, Z., and 14 others.
|
|
<strong>WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia.</strong>
|
|
Parkinsonism Relat. Disord. 94: 54-61, 2022.
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|
[PubMed: 34890876]
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[Full Text: https://doi.org/10.1016/j.parkreldis.2021.11.030]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Stumpf, A. M.
|
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<strong>Personal Communication.</strong>
|
|
Baltimore, Md. 02/17/2022.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Theisen, B. E., Rumyantseva, A., Cohen, J. S., Alcaraz, W. A., Shinde, D. N., Tang, S., Srivastava, S., Pevsner, J., Trifunovic, A., Fatemi, A.
|
|
<strong>Deficiency of WARS2, encoding mitochondrial tryptophanyl tRNA synthetase, causes severe infantile onset leukoencephalopathy.</strong>
|
|
Am. J. Med. Genet. 173A: 2505-2510, 2017.
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[PubMed: 28650581]
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[Full Text: https://doi.org/10.1002/ajmg.a.38339]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Wortmann, S. B., Timal, S., Venselaar, H., Wintjes, L. T., Kopajtich, R., Feichtinger, R. G., Onnekink, C., Mulmeister, M., Brandt, U., Smeitink, J. A., Veltman, J. A., Sperl, W., and 12 others.
|
|
<strong>Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy.</strong>
|
|
Hum. Mutat. 38: 1786-1795, 2017.
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[PubMed: 28905505]
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[Full Text: https://doi.org/10.1002/humu.23340]
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</p>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Anne M. Stumpf - updated : 02/17/2022<br>Cassandra L. Kniffin - updated : 02/11/2022<br>Cassandra L. Kniffin - updated : 10/09/2017<br>Patricia A. Hartz - updated : 5/21/2009
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</span>
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</div>
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</div>
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<br />
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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<div 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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Patti M. Sherman : 3/23/2000
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</span>
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<span class="mim-text-font">
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carol : 02/18/2022<br>alopez : 02/17/2022<br>ckniffin : 02/11/2022<br>carol : 11/13/2017<br>carol : 10/10/2017<br>ckniffin : 10/09/2017<br>carol : 07/20/2016<br>mgross : 05/26/2009<br>terry : 5/21/2009<br>alopez : 8/1/2007<br>mcapotos : 4/7/2000<br>psherman : 3/23/2000
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