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Entry
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- *611592 - PHENYLALANYL-tRNA SYNTHETASE 2, MITOCHONDRIAL; FARS2
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- OMIM
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<p>
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<span class="h4">*611592</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="#geneFunction">Gene Function</a>
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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="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/611592">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000145982;t=ENST00000274680" 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=10667" 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=611592" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<span class="panel-title">
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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=ENSG00000145982;t=ENST00000274680" 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_001318872,NM_001374875,NM_001374876,NM_001374877,NM_001374878,NM_001374879,NM_001375257,NM_001375258,NM_001375259,NM_001375260,NM_006567,XM_006714966,XM_011514247,XM_011514248,XM_011514249,XM_011514251,XM_047418086,XM_047418087,XR_007059196,XR_007059197,XR_007059198,XR_007059199,XR_926027" 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_006567" 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=611592" 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=09946&isoform_id=09946_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/FARS2" 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/3983103,5729820,6841290,18044251,18088902,49457552,55976225,62898407,119575583,189065522,578811360,767939110,767939112,767939114,767939120,974141098,1767344653,1767344670,1767344672,1767344724,1767344731,1767344748,1767344750,1767344759,1767344762,2217359293,2217359304,2462605595,2462605597,2462605599,2462605601,2462605606,2462605610,2462605612" 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/O95363" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=10667" 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=ENSG00000145982;t=ENST00000274680" 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=FARS2" 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=FARS2" 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+10667" 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/FARS2" 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:10667" 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/10667" 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=chr6&hgg_gene=ENST00000274680.9&hgg_start=5249934&hgg_end=5771583&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:21062" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:21062" 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=611592[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=611592[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/FARS2/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000145982" 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=FARS2" 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=FARS2" 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=FARS2" 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=FARS2&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/PA134954893" 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:21062" 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/FBgn0275436.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:1917205" 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/FARS2#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:1917205" 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/10667/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=10667" 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=WBGene00013361;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-070928-38" 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:10667" 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=FARS2&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> 1187506008, 778065005<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>
|
|
611592
|
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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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PHENYLALANYL-tRNA SYNTHETASE 2, MITOCHONDRIAL; FARS2
|
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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>
|
|
</span>
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</p>
|
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</div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
FARS1<br />
|
|
MITOCHONDRIAL PHERS
|
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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">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=FARS2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">FARS2</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/6/33?start=-3&limit=10&highlight=33">6p25.1</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr6:5249934-5771583&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'})">6:5,249,934-5,771,583</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=614946,617046" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/6/33?start=-3&limit=10&highlight=33">
|
|
6p25.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Combined oxidative phosphorylation deficiency 14
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/614946"> 614946 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
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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">
|
|
Spastic paraplegia 77, autosomal recessive
|
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|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/617046"> 617046 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
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<p>Aminoacyl-tRNA synthetases are enzymes that catalyze attachment of amino acids to their cognate tRNAs. Phenylalanyl-tRNA synthetase (PheRS) is a member of the class II aminoacyl-tRNA synthetases (<a href="#3" class="mim-tip-reference" title="Bullard, J. M., Cai, Y.-C., Demeler, B., Spremulli, L. L. <strong>Expression and characterization of a human mitochondrial phenylalanyl-tRNA synthetase.</strong> J. Molec. Biol. 288: 567-577, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10329163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10329163</a>] [<a href="https://doi.org/10.1006/jmbi.1999.2708" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10329163">Bullard et al., 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10329163" 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 screening a human EST database with consensus sequences derived from the conserved regions of the alpha and beta subunits of bacterial PheRS, <a href="#3" class="mim-tip-reference" title="Bullard, J. M., Cai, Y.-C., Demeler, B., Spremulli, L. L. <strong>Expression and characterization of a human mitochondrial phenylalanyl-tRNA synthetase.</strong> J. Molec. Biol. 288: 567-577, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10329163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10329163</a>] [<a href="https://doi.org/10.1006/jmbi.1999.2708" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10329163">Bullard et al. (1999)</a> identified 2 partial FARS2 clones. Sequence analysis determined that 1 clone was a truncated form of the other and that human FARS2 consisted of a single polypeptide chain. The deduced 451-amino acid FARS2 protein has a predicted molecular mass of 49.6 kD and an N-terminal mitochondrial targeting signal. FARS2 shares 42% and 52% amino acid identity with yeast and Drosophila mitochondrial PheRS, respectively, and has no significant homology to the eukaryotic cytoplasmic form (see FARSA; <a href="/entry/602918">602918</a>). FARS2 migrated as a 48-kD band by SDS-PAGE, and gel filtration and velocity sedimentation centrifugation analysis determined that FARS2 is active as a monomer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10329163" 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="#10" class="mim-tip-reference" title="Yang, Y., Liu, W., Fang, Z., Shi, J., Che, F., He, C., Yao, L., Wang, E., Wu, Y. <strong>A newly identified missense mutation in FARS2 causes autosomal-recessive spastic paraplegia.</strong> Hum. Mutat. 37: 165-169, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26553276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26553276</a>] [<a href="https://doi.org/10.1002/humu.22930" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26553276">Yang et al. (2016)</a> found expression of the FARS2 gene in rat Purkinje cells in cerebellum, but not in pyramidal cells of the cerebral cortex or in spinal motor neurons. In the cerebellum, FARS2 colocalized with mitochondrial markers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26553276" 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 aminoacylation assay analysis with expressed tagged-FARS2 in E. coli, <a href="#3" class="mim-tip-reference" title="Bullard, J. M., Cai, Y.-C., Demeler, B., Spremulli, L. L. <strong>Expression and characterization of a human mitochondrial phenylalanyl-tRNA synthetase.</strong> J. Molec. Biol. 288: 567-577, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10329163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10329163</a>] [<a href="https://doi.org/10.1006/jmbi.1999.2708" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10329163">Bullard et al. (1999)</a> showed that FARS2 can charge tRNA with phenylalanine, but at a rate 20- to 30-fold lower than that of yeast cytoplasmic PheRS. By analyzing FARS2 activity under varying concentrations of ATP, they demonstrated that human mitochondrial PheRS requires a high concentration of ATP for maximal activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10329163" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#2" class="mim-tip-reference" title="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 FARS2 gene contains 6 exons and spans 403 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><p><a href="#5" class="mim-tip-reference" title="Elo, J. M., Yadavalli, S. S., Euro, L., Isohanni, P., Gotz, A., Carroll, C. J., Valanne, L., Alkuraya, F. S., Uusimaa, J., Paetau, A., Caruso, E. M., Pihko, H., Ibba, M., Tyynismaa, H., Suomalainen, A. <strong>Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy.</strong> Hum. Molec. Genet. 21: 4521-4529, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22833457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22833457</a>] [<a href="https://doi.org/10.1093/hmg/dds294" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22833457">Elo et al. (2012)</a> stated that the FARS2 gene contains 7 exons, of which exons 2-7 are protein-coding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22833457" 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="#6" class="mim-tip-reference" title="Gross, M. B. <strong>Personal Communication.</strong> Baltimore, Md. 2/1/2018."None>Gross (2018)</a> mapped the FARS2 gene to chromosome 6p25.1 based on an alignment of the FARS2 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AF097441" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AF097441</a>) with the genomic sequence (GRCh38).</p>
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In 3 sibs, born of consanguineous Saudi Arabian parents, with combined oxidative phosphorylation deficiency (COXPD14; <a href="/entry/614946">614946</a>), <a href="#7" class="mim-tip-reference" title="Shamseldin, H. E., Alshammari, M., Al-Sheddi, T., Salih, M. A., Alkhalidi, H., Kentab, A., Repetto, G. M., Hashem, M., Alkuraya, F. S. <strong>Genomic analysis of mitochondrial diseases in a consanguineous population reveals novel candidate disease genes.</strong> J. Med. Genet. 49: 234-241, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22499341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22499341</a>] [<a href="https://doi.org/10.1136/jmedgenet-2012-100836" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22499341">Shamseldin et al. (2012)</a> identified a homozygous mutation in the FARS2 gene (Y144C; <a href="#0001">611592.0001</a>). The mutation was identified by exome sequencing and confirmed by Sanger sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22499341" 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 exome sequencing of 2 sibs with combined oxidative phosphorylation deficiency manifest as fatal infantile epileptic mitochondrial encephalopathy, <a href="#5" class="mim-tip-reference" title="Elo, J. M., Yadavalli, S. S., Euro, L., Isohanni, P., Gotz, A., Carroll, C. J., Valanne, L., Alkuraya, F. S., Uusimaa, J., Paetau, A., Caruso, E. M., Pihko, H., Ibba, M., Tyynismaa, H., Suomalainen, A. <strong>Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy.</strong> Hum. Molec. Genet. 21: 4521-4529, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22833457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22833457</a>] [<a href="https://doi.org/10.1093/hmg/dds294" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22833457">Elo et al. (2012)</a> identified compound heterozygosity for 2 missense mutations in the FARS2 gene (I329T, <a href="#0002">611592.0002</a>; D391V, <a href="#0003">611592.0003</a>). In vitro functional expression studies indicated that these mutations, and the Y144C mutation reported by <a href="#7" class="mim-tip-reference" title="Shamseldin, H. E., Alshammari, M., Al-Sheddi, T., Salih, M. A., Alkhalidi, H., Kentab, A., Repetto, G. M., Hashem, M., Alkuraya, F. S. <strong>Genomic analysis of mitochondrial diseases in a consanguineous population reveals novel candidate disease genes.</strong> J. Med. Genet. 49: 234-241, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22499341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22499341</a>] [<a href="https://doi.org/10.1136/jmedgenet-2012-100836" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22499341">Shamseldin et al. (2012)</a>, all resulted in impaired aminoacylation function and stability of the protein, causing an overall decrease in tRNA charging capacity. The findings indicated that FARS2 mutations cause a mitochondrial translation disorder. The phenotype in all 3 patients was characterized by infantile onset of a fatal encephalopathy with refractory seizures, lack of psychomotor development, and lactic acidosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22499341+22833457" 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 male infant with COXPD14, <a href="#4" class="mim-tip-reference" title="Chen, W., Rehsi, P., Thompson, K., Yeo, M., Stals, K., He, L., Schimmel, P., Chrzanowska-Lightowlers, Z. M. A., Wakeling, E., Taylor, R. W., Kuhle, B. <strong>Clinical and molecular characterization of novel FARS2 variants causing neonatal mitochondrial disease.</strong> Molec. Genet. Metab. 140: 107657, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37523899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37523899</a>] [<a href="https://doi.org/10.1016/j.ymgme.2023.107657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37523899">Chen et al. (2023)</a> identified compound heterozygous mutations in the FARS2 gene (EX2DEL, <a href="#0011">611592.0011</a> and R198L, <a href="#0012">611592.0012</a>). Steady state levels of mtPheRS were reduced in patient fibroblasts and complex I activity was mildly reduced. A crystal structure of FARS2 with the R198L mutation suggested that the mutation results in destabilization of the protein's core region. An aminoacylation assay demonstrated that the R198L mutation resulted in reduced tRNA charging activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37523899" 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>Autosomal Recessive Spastic Paraplegia 77</em></strong></p><p>
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In 4 sibs, born of consanguineous Chinese parents, with autosomal recessive spastic paraplegia-77 (SPG77; <a href="/entry/617046">617046</a>), <a href="#10" class="mim-tip-reference" title="Yang, Y., Liu, W., Fang, Z., Shi, J., Che, F., He, C., Yao, L., Wang, E., Wu, Y. <strong>A newly identified missense mutation in FARS2 causes autosomal-recessive spastic paraplegia.</strong> Hum. Mutat. 37: 165-169, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26553276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26553276</a>] [<a href="https://doi.org/10.1002/humu.22930" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26553276">Yang et al. (2016)</a> identified a homozygous missense mutation in the FARS2 gene (D142Y; <a href="#0005">611592.0005</a>). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies in E. coli showed that the mutation resulted in severely impaired enzyme activity compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26553276" 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 sibs with mitochondrial dysfunction and spastic paraplegia, <a href="#9" class="mim-tip-reference" title="Vernon, H. J., McClellan, R., Batista, D. A. S., Naidu, S. <strong>Mutations in FARS2 and non-fatal mitochondrial dysfunction in two siblings.</strong> Am. J. Med. Genet. 167A: 1147-1151, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25851414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25851414</a>] [<a href="https://doi.org/10.1002/ajmg.a.36993" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25851414">Vernon et al. (2015)</a> identified compound heterozygous mutations in the FARS2 gene: a missense mutation (R429C; <a href="#0006">611592.0006</a>) and an intragenic deletion (<a href="#0007">611592.0007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25851414" 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 unrelated patients with mitochondrial dysfunction and spastic paraplegia, <a href="#8" class="mim-tip-reference" title="Vantroys, E., Larson, A., Friederich, M., Knight, K., Swanson, M. A., Powell, C. A., Smet, J., Vergult, S., De Paepe, B., Seneca, S., Roeyers, H., Menten, B., Minczuk, M., Vanlander, A., Van Hove, J., Van Coster, R. <strong>New insights into the phenotype of FARS2 deficiency.</strong> Molec. Genet. Metab. 122: 172-181, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29126765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29126765</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29126765[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ymgme.2017.10.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29126765">Vantroys et al. (2017)</a> identified compound heterozygous mutations in the FARS2 gene (<a href="#0008">611592.0008</a>-<a href="#0010">611592.0010</a>). FARS2 catalyzes the charging of the tRNA-phe. Compared to normal control fibroblasts, patient fibroblasts showed a decreased amount of Phe-charged tRNA and a decrease in mitochondrial protein synthesis rate, which affected the assembly of OXPHOS complexes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29126765" 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=611592[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397514610 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514610;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=rs397514610" 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=rs397514610" 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=RCV000033044 OR RCV000162158 OR RCV000497519" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000033044, RCV000162158, RCV000497519" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000033044...</a>
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<p>In 2 sibs, born of consanguineous Saudi Arabian parents, with combined oxidative phosphorylation deficiency-14 (COXPD14; <a href="/entry/614946">614946</a>), <a href="#7" class="mim-tip-reference" title="Shamseldin, H. E., Alshammari, M., Al-Sheddi, T., Salih, M. A., Alkhalidi, H., Kentab, A., Repetto, G. M., Hashem, M., Alkuraya, F. S. <strong>Genomic analysis of mitochondrial diseases in a consanguineous population reveals novel candidate disease genes.</strong> J. Med. Genet. 49: 234-241, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22499341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22499341</a>] [<a href="https://doi.org/10.1136/jmedgenet-2012-100836" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22499341">Shamseldin et al. (2012)</a> identified a homozygous 431A-G transition in the FARS2 gene, resulting in a tyr144-to-cys (Y144C) substitution at a highly conserved residue in the catalytic domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in 114 Saudi controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22499341" 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="#5" class="mim-tip-reference" title="Elo, J. M., Yadavalli, S. S., Euro, L., Isohanni, P., Gotz, A., Carroll, C. J., Valanne, L., Alkuraya, F. S., Uusimaa, J., Paetau, A., Caruso, E. M., Pihko, H., Ibba, M., Tyynismaa, H., Suomalainen, A. <strong>Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy.</strong> Hum. Molec. Genet. 21: 4521-4529, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22833457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22833457</a>] [<a href="https://doi.org/10.1093/hmg/dds294" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22833457">Elo et al. (2012)</a> found that the Y144C mutation occurs in the aminoacylation domain on the interface of the anticodon stem-binding domain and may participate in stabilization of the closed structure. In vitro functional expression studies in E. coli indicated that the mutation resulted in decreased affinity for tRNA, causing a decrease in overall tRNA charging capacity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22833457" 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> rs397514611 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514611;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/rs397514611?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=rs397514611" 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=rs397514611" 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=RCV000033045" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000033045" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000033045</a>
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<p>In 2 Finnish sibs with combined oxidative phosphorylation deficiency-14 (COXPD14; <a href="/entry/614946">614946</a>), <a href="#5" class="mim-tip-reference" title="Elo, J. M., Yadavalli, S. S., Euro, L., Isohanni, P., Gotz, A., Carroll, C. J., Valanne, L., Alkuraya, F. S., Uusimaa, J., Paetau, A., Caruso, E. M., Pihko, H., Ibba, M., Tyynismaa, H., Suomalainen, A. <strong>Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy.</strong> Hum. Molec. Genet. 21: 4521-4529, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22833457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22833457</a>] [<a href="https://doi.org/10.1093/hmg/dds294" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22833457">Elo et al. (2012)</a> identified compound heterozygosity for 2 mutations in the FARS2 gene: a 986T-C transition in exon 5 resulting in an ile329-to-thr (I329T) substitution, and a 1172A-T transversion in exon 6 resulting in an asp391-to-val (D391V; <a href="#0003">611592.0003</a>) substitution. Each unaffected parent was heterozygous for 1 of the mutations, neither of which was found in 400 Finnish control chromosomes or in the 1000 Genomes Project database. Both mutations occurred at highly conserved residues. The ile329 residue is part of the ATP-binding site in the aminoacylation domain, whereas asp391 is in the anticodon stem-binding domain. In vitro functional expression studies in E. coli indicated that the I329T mutation resulted in a 4-fold decrease in the catalytic activity of amino acid activation due to a decreased affinity for ATP. The D391V mutation was predicted to result in a decrease in phe binding, causing a decrease in aminoacylation activity. Both mutations also caused decreased stabilization of the proteins, resulting in a decrease in overall charging capacity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22833457" 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> rs397514612 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514612;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/rs397514612?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=rs397514612" 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=rs397514612" 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 asp391-to-val (D391V) mutation in the FARS2 gene that was found in compound heterozygous state in patients with combined oxidative phosphorylation deficiency-14 (COXPD14; <a href="/entry/614946">614946</a>) by <a href="#5" class="mim-tip-reference" title="Elo, J. M., Yadavalli, S. S., Euro, L., Isohanni, P., Gotz, A., Carroll, C. J., Valanne, L., Alkuraya, F. S., Uusimaa, J., Paetau, A., Caruso, E. M., Pihko, H., Ibba, M., Tyynismaa, H., Suomalainen, A. <strong>Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy.</strong> Hum. Molec. Genet. 21: 4521-4529, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22833457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22833457</a>] [<a href="https://doi.org/10.1093/hmg/dds294" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22833457">Elo et al. (2012)</a>, see <a href="#0002">611592.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22833457" 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 COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 14</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> rs764427452 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs764427452;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/rs764427452?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=rs764427452" 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=rs764427452" 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=RCV000239485" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000239485" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000239485</a>
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<p>In a 2.5-year-old boy, born of unrelated British Caucasian parents, with a variant of combined oxidative phosphorylation deficiency-14 (COXPD14; <a href="/entry/614946">614946</a>), <a href="#1" class="mim-tip-reference" title="Almalki, A., Alston, C. L., Parker, A., Simonic, I., Mehta, S. G., He, L., Reza, M., Oliveira, J. M. A., Lightowlers, R. N., McFarland, R., Taylor, R. W., Chrzanowska-Lightowlers, Z. M. A. <strong>Mutation of the human mitochondrial phenylalanine-tRNA synthetase causes infantile-onset epilepsy and cytochrome c oxidase deficiency.</strong> Biochim. Biophys. Acta 1842: 56-64, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24161539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24161539</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24161539[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.bbadis.2013.10.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24161539">Almalki et al. (2014)</a> identified a maternally inherited heterozygous c.973G-T transversion (c.973G-T, NM_006567.3) in exon 5 of the FARS2 gene, resulting in an asp325-to-tyr (D325Y) substitution at a conserved residue in the catalytic domain that is involved in ATP binding. High resolution array CGH showed that the other allele carried a paternally inherited 88-kb interstitial deletion of chromosome 6p25.1 including the promoter and untranslated exon 1 of FARS2 and the 3-prime exons of the LYRM4 (<a href="/entry/613311">613311</a>) gene. A missense mutation in the LYRM4 gene (R68L) has been identified in a family with COXPD19 (<a href="/entry/615595">615595</a>). Analysis of tissues from the patient reported by <a href="#1" class="mim-tip-reference" title="Almalki, A., Alston, C. L., Parker, A., Simonic, I., Mehta, S. G., He, L., Reza, M., Oliveira, J. M. A., Lightowlers, R. N., McFarland, R., Taylor, R. W., Chrzanowska-Lightowlers, Z. M. A. <strong>Mutation of the human mitochondrial phenylalanine-tRNA synthetase causes infantile-onset epilepsy and cytochrome c oxidase deficiency.</strong> Biochim. Biophys. Acta 1842: 56-64, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24161539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24161539</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24161539[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.bbadis.2013.10.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24161539">Almalki et al. (2014)</a> showed an isolated complex IV deficiency in skeletal muscle and myoblasts, but not in fibroblasts. Northern and Western blot analysis of patient skeletal muscle showed decreased levels of FARS2 mRNA and protein, respectively, compared to controls, and in vitro functional expression assays showed that the D325Y mutant protein had no detectable enzyme activity and no detectable ATP binding. However, patient myoblasts did not show impaired synthesis of mitochondrial proteins, and there was not a decrease in mtDNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24161539" 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 SPASTIC PARAPLEGIA 77, AUTOSOMAL RECESSIVE</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> rs145555213 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs145555213;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/rs145555213?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=rs145555213" 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=rs145555213" 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=RCV000239526" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000239526" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000239526</a>
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<p>In 4 sibs, born of consanguineous Chinese parents, with autosomal recessive spastic paraplegia-77 (SPG77; <a href="/entry/617046">617046</a>), <a href="#10" class="mim-tip-reference" title="Yang, Y., Liu, W., Fang, Z., Shi, J., Che, F., He, C., Yao, L., Wang, E., Wu, Y. <strong>A newly identified missense mutation in FARS2 causes autosomal-recessive spastic paraplegia.</strong> Hum. Mutat. 37: 165-169, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26553276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26553276</a>] [<a href="https://doi.org/10.1002/humu.22930" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26553276">Yang et al. (2016)</a> identified a homozygous c.424G-T transversion (c.424G-T, NM_006567.3) in exon 2 of the FARS2 gene, resulting in an asp142-to-tyr (D142Y) substitution at a highly conserved residue in the catalytic motif of aminoacylation at the interface of the anticodon stem-binding domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and was not found in the dbSNP (build 132) or 1000 Genomes Project databases. In vitro functional expression studies in E. coli showed that the mutation resulted in severely impaired enzyme activity compared to wildtype. The aminoacylation activity was impaired at the first aminoacylation step and at the last transfer step. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26553276" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 SPASTIC PARAPLEGIA 77, AUTOSOMAL RECESSIVE</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> rs775690041 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs775690041;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/rs775690041?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=rs775690041" 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=rs775690041" 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=RCV000197201 OR RCV000578139 OR RCV001378476" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000197201, RCV000578139, RCV001378476" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000197201...</a>
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<p>In 2 sibs with mitochondrial dysfunction and spastic paraplegia (SPG77; <a href="/entry/617046">617046</a>), <a href="#9" class="mim-tip-reference" title="Vernon, H. J., McClellan, R., Batista, D. A. S., Naidu, S. <strong>Mutations in FARS2 and non-fatal mitochondrial dysfunction in two siblings.</strong> Am. J. Med. Genet. 167A: 1147-1151, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25851414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25851414</a>] [<a href="https://doi.org/10.1002/ajmg.a.36993" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25851414">Vernon et al. (2015)</a> identified compound heterozygous mutations in the FARS2 gene: a paternally inherited c.1255C-T transition in exon 7, resulting in an arg419-to-cys (R419C) substitution at a conserved location in the phenylalanyl-RNA synthetase C-terminal domain, and a maternally inherited 116-kb interstitial deletion (nucleotides 5,610,223-5,726,369), including all of exon 6 and parts of introns 5 and 6. The mutations, which were found by exome sequencing and SNP array, respectively, were confirmed by Sanger sequencing. The missense mutation was not found in 6,500 individuals in the NHBLI Exome Sequencing Project database. Functional studies of the variants were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25851414" 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=RCV000578146" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000578146" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000578146</a>
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<p>For discussion of the 116-kb interstitial deletion in the FARS2 gene that was found in compound heterozygous state in 2 sibs with mitochondrial dysfunction and spastic paraplegia (SPG77; <a href="/entry/617046">617046</a>) by <a href="#9" class="mim-tip-reference" title="Vernon, H. J., McClellan, R., Batista, D. A. S., Naidu, S. <strong>Mutations in FARS2 and non-fatal mitochondrial dysfunction in two siblings.</strong> Am. J. Med. Genet. 167A: 1147-1151, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25851414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25851414</a>] [<a href="https://doi.org/10.1002/ajmg.a.36993" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25851414">Vernon et al. (2015)</a>, see <a href="#0006">611592.0006</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25851414" 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> rs751459058 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs751459058;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/rs751459058?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=rs751459058" 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=rs751459058" 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=RCV000200808 OR RCV000525331 OR RCV000578164 OR RCV000622524 OR RCV003156085 OR RCV004751360" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000200808, RCV000525331, RCV000578164, RCV000622524, RCV003156085, RCV004751360" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000200808...</a>
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<p>In 2 unrelated patients with mitochondrial dysfunction and spastic paraplegia (SPG77; <a href="/entry/617046">617046</a>), <a href="#8" class="mim-tip-reference" title="Vantroys, E., Larson, A., Friederich, M., Knight, K., Swanson, M. A., Powell, C. A., Smet, J., Vergult, S., De Paepe, B., Seneca, S., Roeyers, H., Menten, B., Minczuk, M., Vanlander, A., Van Hove, J., Van Coster, R. <strong>New insights into the phenotype of FARS2 deficiency.</strong> Molec. Genet. Metab. 122: 172-181, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29126765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29126765</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29126765[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ymgme.2017.10.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29126765">Vantroys et al. (2017)</a> identified compound heterozygous mutations in the FARS2 gene: a c.1082C-T transition (c.1082C-T, NM_006567.4) in exon 6, resulting in a pro361-to-leu (P361L) substitution in the anticodon binding domain, in both probands, combined with a c.461C-T transition in exon 2, resulting in an ala154-to-val (A154V; <a href="#0009">611592.0009</a>) substitution in the catalytic domain, in proband 1, and a 3-bp deletion (c.521_523delTGG), resulting in deletion of val174 (<a href="#0010">611592.0010</a>) in the catalytic domain, in proband 2. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. The P361L and A154V had a prevalence of 15/60,675 and 2/60,594, respectively, in the ExAC database, whereas V174del was not found in ExAC. Compared with normal control fibroblasts, patient fibroblasts showed a decreased amount of Phe-charged tRNA and a decrease in mitochondrial protein synthesis rate, which affected the assembly of OXPHOS complexes: complex IV in proband 1 and complex I in proband 2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29126765" 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>.0009 SPASTIC PARAPLEGIA 77, AUTOSOMAL RECESSIVE</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> rs749588235 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs749588235;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/rs749588235?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=rs749588235" 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=rs749588235" 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=RCV000578201 OR RCV001246829" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000578201, RCV001246829" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000578201...</a>
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<p>For discussion of the c.461C-T transition (c.461C-T, NM_006567.4) in exon 2 of the FARS2 gene, resulting in an ala154-to-val (A154V) substitution, that was found in compound heterozygous state in a patient with spastic paraplegia-77 (SPG77; <a href="/entry/617046">617046</a>) by <a href="#8" class="mim-tip-reference" title="Vantroys, E., Larson, A., Friederich, M., Knight, K., Swanson, M. A., Powell, C. A., Smet, J., Vergult, S., De Paepe, B., Seneca, S., Roeyers, H., Menten, B., Minczuk, M., Vanlander, A., Van Hove, J., Van Coster, R. <strong>New insights into the phenotype of FARS2 deficiency.</strong> Molec. Genet. Metab. 122: 172-181, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29126765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29126765</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29126765[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ymgme.2017.10.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29126765">Vantroys et al. (2017)</a>, see <a href="#0008">611592.0008</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29126765" 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>.0010 SPASTIC PARAPLEGIA 77, AUTOSOMAL RECESSIVE</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">rs1554169392 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1554169392;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=rs1554169392" 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=rs1554169392" 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=RCV000578192 OR RCV001341117" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000578192, RCV001341117" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000578192...</a>
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<p>For discussion of the 3-bp deletion (c.521_523delTGG, NM_006567.4) in the FARS2 gene, resulting in a deletion of val174 (V174del), that was found in compound heterozygous state in a patient with spastic paraplegia-77 (SPG77; <a href="/entry/617046">617046</a>) by <a href="#8" class="mim-tip-reference" title="Vantroys, E., Larson, A., Friederich, M., Knight, K., Swanson, M. A., Powell, C. A., Smet, J., Vergult, S., De Paepe, B., Seneca, S., Roeyers, H., Menten, B., Minczuk, M., Vanlander, A., Van Hove, J., Van Coster, R. <strong>New insights into the phenotype of FARS2 deficiency.</strong> Molec. Genet. Metab. 122: 172-181, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29126765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29126765</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29126765[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ymgme.2017.10.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29126765">Vantroys et al. (2017)</a>, see <a href="#0008">611592.0008</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29126765" 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>.0011 COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 14</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003459880" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003459880" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003459880</a>
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<p>In a male infant with combined oxidative phosphorylation deficiency-14 (COXPD14; <a href="/entry/614946">614946</a>), <a href="#4" class="mim-tip-reference" title="Chen, W., Rehsi, P., Thompson, K., Yeo, M., Stals, K., He, L., Schimmel, P., Chrzanowska-Lightowlers, Z. M. A., Wakeling, E., Taylor, R. W., Kuhle, B. <strong>Clinical and molecular characterization of novel FARS2 variants causing neonatal mitochondrial disease.</strong> Molec. Genet. Metab. 140: 107657, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37523899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37523899</a>] [<a href="https://doi.org/10.1016/j.ymgme.2023.107657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37523899">Chen et al. (2023)</a> identified compound heterozygous mutations in the FARS2 gene: a deletion of exon 2 (NM_006567.5), the first coding exon, and a c.593G-T transversion, resulting in an arg198-to-leu (R198L; 611592.0012) substitution. The mutations were identified by trio whole-exome sequencing, and the parents were shown to be mutation carriers. The R198L mutation was present in the gnomAD database in 1 of 125,000 alleles and was not present in homozygosity. Steady state levels of mtPheRS were reduced in patient fibroblasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37523899" 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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FARS2, ARG198LEU
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003459881" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003459881" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003459881</a>
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<p>For discussion of the c.593G-T transversion (c.593G-T, NM_006567.5) in the FARS2 gene that was found in compound heterozygous state in an infant with combined oxidative phosphorylation deficiency-14 (COXPD14; <a href="/entry/614946">614946</a>) by <a href="#4" class="mim-tip-reference" title="Chen, W., Rehsi, P., Thompson, K., Yeo, M., Stals, K., He, L., Schimmel, P., Chrzanowska-Lightowlers, Z. M. A., Wakeling, E., Taylor, R. W., Kuhle, B. <strong>Clinical and molecular characterization of novel FARS2 variants causing neonatal mitochondrial disease.</strong> Molec. Genet. Metab. 140: 107657, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37523899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37523899</a>] [<a href="https://doi.org/10.1016/j.ymgme.2023.107657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37523899">Chen et al. (2023)</a>, see <a href="#0002">611592.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37523899" 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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Almalki, A., Alston, C. L., Parker, A., Simonic, I., Mehta, S. G., He, L., Reza, M., Oliveira, J. M. A., Lightowlers, R. N., McFarland, R., Taylor, R. W., Chrzanowska-Lightowlers, Z. M. A.
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<strong>Mutation of the human mitochondrial phenylalanine-tRNA synthetase causes infantile-onset epilepsy and cytochrome c oxidase deficiency.</strong>
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Biochim. Biophys. Acta 1842: 56-64, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24161539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24161539</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24161539[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=24161539" 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.bbadis.2013.10.008" target="_blank">Full Text</a>]
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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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Bullard, J. M., Cai, Y.-C., Demeler, B., Spremulli, L. L.
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<strong>Expression and characterization of a human mitochondrial phenylalanyl-tRNA synthetase.</strong>
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J. Molec. Biol. 288: 567-577, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10329163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10329163</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10329163" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/jmbi.1999.2708" 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="4" class="mim-anchor"></a>
|
|
<a id="Chen2023" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Chen, W., Rehsi, P., Thompson, K., Yeo, M., Stals, K., He, L., Schimmel, P., Chrzanowska-Lightowlers, Z. M. A., Wakeling, E., Taylor, R. W., Kuhle, B.
|
|
<strong>Clinical and molecular characterization of novel FARS2 variants causing neonatal mitochondrial disease.</strong>
|
|
Molec. Genet. Metab. 140: 107657, 2023.
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|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37523899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37523899</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37523899" 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.ymgme.2023.107657" 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="5" class="mim-anchor"></a>
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<a id="Elo2012" class="mim-anchor"></a>
|
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<div class="">
|
|
<p class="mim-text-font">
|
|
Elo, J. M., Yadavalli, S. S., Euro, L., Isohanni, P., Gotz, A., Carroll, C. J., Valanne, L., Alkuraya, F. S., Uusimaa, J., Paetau, A., Caruso, E. M., Pihko, H., Ibba, M., Tyynismaa, H., Suomalainen, A.
|
|
<strong>Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy.</strong>
|
|
Hum. Molec. Genet. 21: 4521-4529, 2012.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22833457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22833457</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22833457" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/dds294" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="6" class="mim-anchor"></a>
|
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<a id="Gross2018" class="mim-anchor"></a>
|
|
<div class="">
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|
<p class="mim-text-font">
|
|
Gross, M. B.
|
|
<strong>Personal Communication.</strong>
|
|
Baltimore, Md. 2/1/2018.
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</p>
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</div>
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</li>
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<li>
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<a id="7" class="mim-anchor"></a>
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<a id="Shamseldin2012" class="mim-anchor"></a>
|
|
<div class="">
|
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<p class="mim-text-font">
|
|
Shamseldin, H. E., Alshammari, M., Al-Sheddi, T., Salih, M. A., Alkhalidi, H., Kentab, A., Repetto, G. M., Hashem, M., Alkuraya, F. S.
|
|
<strong>Genomic analysis of mitochondrial diseases in a consanguineous population reveals novel candidate disease genes.</strong>
|
|
J. Med. Genet. 49: 234-241, 2012.
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|
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22499341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22499341</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22499341" 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/10.1136/jmedgenet-2012-100836" 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="Vantroys2017" class="mim-anchor"></a>
|
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<div class="">
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<p class="mim-text-font">
|
|
Vantroys, E., Larson, A., Friederich, M., Knight, K., Swanson, M. A., Powell, C. A., Smet, J., Vergult, S., De Paepe, B., Seneca, S., Roeyers, H., Menten, B., Minczuk, M., Vanlander, A., Van Hove, J., Van Coster, R.
|
|
<strong>New insights into the phenotype of FARS2 deficiency.</strong>
|
|
Molec. Genet. Metab. 122: 172-181, 2017.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29126765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29126765</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29126765[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=29126765" 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.ymgme.2017.10.004" 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="Vernon2015" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
|
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Vernon, H. J., McClellan, R., Batista, D. A. S., Naidu, S.
|
|
<strong>Mutations in FARS2 and non-fatal mitochondrial dysfunction in two siblings.</strong>
|
|
Am. J. Med. Genet. 167A: 1147-1151, 2015.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25851414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25851414</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25851414" 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.36993" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="10" class="mim-anchor"></a>
|
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<a id="Yang2016" class="mim-anchor"></a>
|
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<div class="">
|
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<p class="mim-text-font">
|
|
Yang, Y., Liu, W., Fang, Z., Shi, J., Che, F., He, C., Yao, L., Wang, E., Wu, Y.
|
|
<strong>A newly identified missense mutation in FARS2 causes autosomal-recessive spastic paraplegia.</strong>
|
|
Hum. Mutat. 37: 165-169, 2016.
|
|
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|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26553276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26553276</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26553276" 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.22930" 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">
|
|
Hilary J. Vernon - updated : 12/21/2023
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</span>
|
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</div>
|
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</div>
|
|
<div class="row collapse" id="mimCollapseContributors">
|
|
<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">
|
|
Matthew B. Gross - updated : 02/01/2018<br>Ada Hamosh - updated : 01/30/2018<br>Ada Hamosh - updated : 01/29/2018<br>Cassandra L. Kniffin - updated : 07/21/2016<br>Cassandra L. Kniffin - updated : 11/28/2012<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">
|
|
<span class="text-nowrap mim-text-font">
|
|
Creation Date:
|
|
</span>
|
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</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
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Stefanie A. Nelson : 11/8/2007
|
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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>
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
carol : 12/21/2023
|
|
</span>
|
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</div>
|
|
</div>
|
|
<div class="row collapse" id="mimCollapseEditHistory">
|
|
<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">
|
|
<span class="mim-text-font">
|
|
carol : 12/18/2019<br>mgross : 02/01/2018<br>carol : 01/30/2018<br>carol : 01/29/2018<br>carol : 07/29/2016<br>carol : 07/28/2016<br>ckniffin : 07/21/2016<br>mcolton : 05/12/2015<br>carol : 12/3/2012<br>ckniffin : 11/28/2012<br>mgross : 5/26/2009<br>terry : 5/21/2009<br>wwang : 11/8/2007
|
|
</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">
|
|
|
|
<div>
|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
<strong>*</strong> 611592
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
PHENYLALANYL-tRNA SYNTHETASE 2, MITOCHONDRIAL; FARS2
|
|
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
<div>
|
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<br />
|
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</div>
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<div>
|
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<div >
|
|
<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
FARS1<br />
|
|
MITOCHONDRIAL PHERS
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: FARS2</em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
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<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
|
|
<strong>SNOMEDCT:</strong> 1187506008, 778065005;
|
|
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</span>
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</p>
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</div>
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<div>
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<br />
|
|
</div>
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<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: 6p25.1
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 6:5,249,934-5,771,583 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
6p25.1
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Combined oxidative phosphorylation deficiency 14
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
614946
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Spastic paraplegia 77, autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
617046
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Aminoacyl-tRNA synthetases are enzymes that catalyze attachment of amino acids to their cognate tRNAs. Phenylalanyl-tRNA synthetase (PheRS) is a member of the class II aminoacyl-tRNA synthetases (Bullard et al., 1999). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>By screening a human EST database with consensus sequences derived from the conserved regions of the alpha and beta subunits of bacterial PheRS, Bullard et al. (1999) identified 2 partial FARS2 clones. Sequence analysis determined that 1 clone was a truncated form of the other and that human FARS2 consisted of a single polypeptide chain. The deduced 451-amino acid FARS2 protein has a predicted molecular mass of 49.6 kD and an N-terminal mitochondrial targeting signal. FARS2 shares 42% and 52% amino acid identity with yeast and Drosophila mitochondrial PheRS, respectively, and has no significant homology to the eukaryotic cytoplasmic form (see FARSA; 602918). FARS2 migrated as a 48-kD band by SDS-PAGE, and gel filtration and velocity sedimentation centrifugation analysis determined that FARS2 is active as a monomer. </p><p>Yang et al. (2016) found expression of the FARS2 gene in rat Purkinje cells in cerebellum, but not in pyramidal cells of the cerebral cortex or in spinal motor neurons. In the cerebellum, FARS2 colocalized with mitochondrial markers. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By aminoacylation assay analysis with expressed tagged-FARS2 in E. coli, Bullard et al. (1999) showed that FARS2 can charge tRNA with phenylalanine, but at a rate 20- to 30-fold lower than that of yeast cytoplasmic PheRS. By analyzing FARS2 activity under varying concentrations of ATP, they demonstrated that human mitochondrial PheRS requires a high concentration of ATP for maximal activity. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Bonnefond et al. (2005) determined that the FARS2 gene contains 6 exons and spans 403 kb. </p><p>Elo et al. (2012) stated that the FARS2 gene contains 7 exons, of which exons 2-7 are protein-coding. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Gross (2018) mapped the FARS2 gene to chromosome 6p25.1 based on an alignment of the FARS2 sequence (GenBank AF097441) with the genomic sequence (GRCh38).</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Combined Oxidative Phosphorylation Deficiency 14</em></strong></p><p>
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|
In 3 sibs, born of consanguineous Saudi Arabian parents, with combined oxidative phosphorylation deficiency (COXPD14; 614946), Shamseldin et al. (2012) identified a homozygous mutation in the FARS2 gene (Y144C; 611592.0001). The mutation was identified by exome sequencing and confirmed by Sanger sequencing. </p><p>By exome sequencing of 2 sibs with combined oxidative phosphorylation deficiency manifest as fatal infantile epileptic mitochondrial encephalopathy, Elo et al. (2012) identified compound heterozygosity for 2 missense mutations in the FARS2 gene (I329T, 611592.0002; D391V, 611592.0003). In vitro functional expression studies indicated that these mutations, and the Y144C mutation reported by Shamseldin et al. (2012), all resulted in impaired aminoacylation function and stability of the protein, causing an overall decrease in tRNA charging capacity. The findings indicated that FARS2 mutations cause a mitochondrial translation disorder. The phenotype in all 3 patients was characterized by infantile onset of a fatal encephalopathy with refractory seizures, lack of psychomotor development, and lactic acidosis. </p><p>In a male infant with COXPD14, Chen et al. (2023) identified compound heterozygous mutations in the FARS2 gene (EX2DEL, 611592.0011 and R198L, 611592.0012). Steady state levels of mtPheRS were reduced in patient fibroblasts and complex I activity was mildly reduced. A crystal structure of FARS2 with the R198L mutation suggested that the mutation results in destabilization of the protein's core region. An aminoacylation assay demonstrated that the R198L mutation resulted in reduced tRNA charging activity. </p><p><strong><em>Autosomal Recessive Spastic Paraplegia 77</em></strong></p><p>
|
|
In 4 sibs, born of consanguineous Chinese parents, with autosomal recessive spastic paraplegia-77 (SPG77; 617046), Yang et al. (2016) identified a homozygous missense mutation in the FARS2 gene (D142Y; 611592.0005). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies in E. coli showed that the mutation resulted in severely impaired enzyme activity compared to wildtype. </p><p>In 2 sibs with mitochondrial dysfunction and spastic paraplegia, Vernon et al. (2015) identified compound heterozygous mutations in the FARS2 gene: a missense mutation (R429C; 611592.0006) and an intragenic deletion (611592.0007). </p><p>In 2 unrelated patients with mitochondrial dysfunction and spastic paraplegia, Vantroys et al. (2017) identified compound heterozygous mutations in the FARS2 gene (611592.0008-611592.0010). FARS2 catalyzes the charging of the tRNA-phe. Compared to normal control fibroblasts, patient fibroblasts showed a decreased amount of Phe-charged tRNA and a decrease in mitochondrial protein synthesis rate, which affected the assembly of OXPHOS complexes. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>12 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0001 COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 14</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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FARS2, TYR144CYS
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<br />
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SNP: rs397514610,
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ClinVar: RCV000033044, RCV000162158, RCV000497519
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In 2 sibs, born of consanguineous Saudi Arabian parents, with combined oxidative phosphorylation deficiency-14 (COXPD14; 614946), Shamseldin et al. (2012) identified a homozygous 431A-G transition in the FARS2 gene, resulting in a tyr144-to-cys (Y144C) substitution at a highly conserved residue in the catalytic domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in 114 Saudi controls. </p><p>Elo et al. (2012) found that the Y144C mutation occurs in the aminoacylation domain on the interface of the anticodon stem-binding domain and may participate in stabilization of the closed structure. In vitro functional expression studies in E. coli indicated that the mutation resulted in decreased affinity for tRNA, causing a decrease in overall tRNA charging capacity. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 14</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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FARS2, ILE329THR
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<br />
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SNP: rs397514611,
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gnomAD: rs397514611,
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ClinVar: RCV000033045
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 2 Finnish sibs with combined oxidative phosphorylation deficiency-14 (COXPD14; 614946), Elo et al. (2012) identified compound heterozygosity for 2 mutations in the FARS2 gene: a 986T-C transition in exon 5 resulting in an ile329-to-thr (I329T) substitution, and a 1172A-T transversion in exon 6 resulting in an asp391-to-val (D391V; 611592.0003) substitution. Each unaffected parent was heterozygous for 1 of the mutations, neither of which was found in 400 Finnish control chromosomes or in the 1000 Genomes Project database. Both mutations occurred at highly conserved residues. The ile329 residue is part of the ATP-binding site in the aminoacylation domain, whereas asp391 is in the anticodon stem-binding domain. In vitro functional expression studies in E. coli indicated that the I329T mutation resulted in a 4-fold decrease in the catalytic activity of amino acid activation due to a decreased affinity for ATP. The D391V mutation was predicted to result in a decrease in phe binding, causing a decrease in aminoacylation activity. Both mutations also caused decreased stabilization of the proteins, resulting in a decrease in overall charging capacity. </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 14</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
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|
|
FARS2, ASP391VAL
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<br />
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|
|
SNP: rs397514612,
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|
|
gnomAD: rs397514612,
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|
|
ClinVar: RCV000033046
|
|
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|
|
</span>
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|
</div>
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the asp391-to-val (D391V) mutation in the FARS2 gene that was found in compound heterozygous state in patients with combined oxidative phosphorylation deficiency-14 (COXPD14; 614946) by Elo et al. (2012), see 611592.0002. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 14</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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<div>
|
|
<span class="mim-text-font">
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|
|
|
FARS2, ASP325TYR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs764427452,
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|
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|
|
|
gnomAD: rs764427452,
|
|
|
|
|
|
ClinVar: RCV000239485
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 2.5-year-old boy, born of unrelated British Caucasian parents, with a variant of combined oxidative phosphorylation deficiency-14 (COXPD14; 614946), Almalki et al. (2014) identified a maternally inherited heterozygous c.973G-T transversion (c.973G-T, NM_006567.3) in exon 5 of the FARS2 gene, resulting in an asp325-to-tyr (D325Y) substitution at a conserved residue in the catalytic domain that is involved in ATP binding. High resolution array CGH showed that the other allele carried a paternally inherited 88-kb interstitial deletion of chromosome 6p25.1 including the promoter and untranslated exon 1 of FARS2 and the 3-prime exons of the LYRM4 (613311) gene. A missense mutation in the LYRM4 gene (R68L) has been identified in a family with COXPD19 (615595). Analysis of tissues from the patient reported by Almalki et al. (2014) showed an isolated complex IV deficiency in skeletal muscle and myoblasts, but not in fibroblasts. Northern and Western blot analysis of patient skeletal muscle showed decreased levels of FARS2 mRNA and protein, respectively, compared to controls, and in vitro functional expression assays showed that the D325Y mutant protein had no detectable enzyme activity and no detectable ATP binding. However, patient myoblasts did not show impaired synthesis of mitochondrial proteins, and there was not a decrease in mtDNA. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
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|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 SPASTIC PARAPLEGIA 77, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FARS2, ASP142TYR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs145555213,
|
|
|
|
|
|
gnomAD: rs145555213,
|
|
|
|
|
|
ClinVar: RCV000239526
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 sibs, born of consanguineous Chinese parents, with autosomal recessive spastic paraplegia-77 (SPG77; 617046), Yang et al. (2016) identified a homozygous c.424G-T transversion (c.424G-T, NM_006567.3) in exon 2 of the FARS2 gene, resulting in an asp142-to-tyr (D142Y) substitution at a highly conserved residue in the catalytic motif of aminoacylation at the interface of the anticodon stem-binding domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and was not found in the dbSNP (build 132) or 1000 Genomes Project databases. In vitro functional expression studies in E. coli showed that the mutation resulted in severely impaired enzyme activity compared to wildtype. The aminoacylation activity was impaired at the first aminoacylation step and at the last transfer step. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 SPASTIC PARAPLEGIA 77, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FARS2, ARG419CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs775690041,
|
|
|
|
|
|
gnomAD: rs775690041,
|
|
|
|
|
|
ClinVar: RCV000197201, RCV000578139, RCV001378476
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs with mitochondrial dysfunction and spastic paraplegia (SPG77; 617046), Vernon et al. (2015) identified compound heterozygous mutations in the FARS2 gene: a paternally inherited c.1255C-T transition in exon 7, resulting in an arg419-to-cys (R419C) substitution at a conserved location in the phenylalanyl-RNA synthetase C-terminal domain, and a maternally inherited 116-kb interstitial deletion (nucleotides 5,610,223-5,726,369), including all of exon 6 and parts of introns 5 and 6. The mutations, which were found by exome sequencing and SNP array, respectively, were confirmed by Sanger sequencing. The missense mutation was not found in 6,500 individuals in the NHBLI Exome Sequencing Project database. Functional studies of the variants were not performed. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 SPASTIC PARAPLEGIA 77, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FARS2, 116-KB DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000578146
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 116-kb interstitial deletion in the FARS2 gene that was found in compound heterozygous state in 2 sibs with mitochondrial dysfunction and spastic paraplegia (SPG77; 617046) by Vernon et al. (2015), see 611592.0006. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 SPASTIC PARAPLEGIA 77, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FARS2, PRO361LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs751459058,
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|
|
|
|
|
gnomAD: rs751459058,
|
|
|
|
|
|
ClinVar: RCV000200808, RCV000525331, RCV000578164, RCV000622524, RCV003156085, RCV004751360
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated patients with mitochondrial dysfunction and spastic paraplegia (SPG77; 617046), Vantroys et al. (2017) identified compound heterozygous mutations in the FARS2 gene: a c.1082C-T transition (c.1082C-T, NM_006567.4) in exon 6, resulting in a pro361-to-leu (P361L) substitution in the anticodon binding domain, in both probands, combined with a c.461C-T transition in exon 2, resulting in an ala154-to-val (A154V; 611592.0009) substitution in the catalytic domain, in proband 1, and a 3-bp deletion (c.521_523delTGG), resulting in deletion of val174 (611592.0010) in the catalytic domain, in proband 2. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. The P361L and A154V had a prevalence of 15/60,675 and 2/60,594, respectively, in the ExAC database, whereas V174del was not found in ExAC. Compared with normal control fibroblasts, patient fibroblasts showed a decreased amount of Phe-charged tRNA and a decrease in mitochondrial protein synthesis rate, which affected the assembly of OXPHOS complexes: complex IV in proband 1 and complex I in proband 2. </p>
|
|
</span>
|
|
</div>
|
|
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|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 SPASTIC PARAPLEGIA 77, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
FARS2, ALA154VAL
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|
|
<br />
|
|
|
|
SNP: rs749588235,
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|
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|
|
|
gnomAD: rs749588235,
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|
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|
|
|
ClinVar: RCV000578201, RCV001246829
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|
|
</span>
|
|
</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.461C-T transition (c.461C-T, NM_006567.4) in exon 2 of the FARS2 gene, resulting in an ala154-to-val (A154V) substitution, that was found in compound heterozygous state in a patient with spastic paraplegia-77 (SPG77; 617046) by Vantroys et al. (2017), see 611592.0008. </p>
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<span class="mim-font">
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<strong>.0010 SPASTIC PARAPLEGIA 77, AUTOSOMAL RECESSIVE</strong>
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</h4>
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<span class="mim-text-font">
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FARS2, 3-BP DEL, 521TGG
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<br />
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SNP: rs1554169392,
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ClinVar: RCV000578192, RCV001341117
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<span class="mim-text-font">
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<p>For discussion of the 3-bp deletion (c.521_523delTGG, NM_006567.4) in the FARS2 gene, resulting in a deletion of val174 (V174del), that was found in compound heterozygous state in a patient with spastic paraplegia-77 (SPG77; 617046) by Vantroys et al. (2017), see 611592.0008. </p>
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<span class="mim-font">
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<strong>.0011 COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 14</strong>
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</h4>
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<span class="mim-text-font">
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FARS2, EX2DEL
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<br />
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ClinVar: RCV003459880
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<p>In a male infant with combined oxidative phosphorylation deficiency-14 (COXPD14; 614946), Chen et al. (2023) identified compound heterozygous mutations in the FARS2 gene: a deletion of exon 2 (NM_006567.5), the first coding exon, and a c.593G-T transversion, resulting in an arg198-to-leu (R198L; 611592.0012) substitution. The mutations were identified by trio whole-exome sequencing, and the parents were shown to be mutation carriers. The R198L mutation was present in the gnomAD database in 1 of 125,000 alleles and was not present in homozygosity. Steady state levels of mtPheRS were reduced in patient fibroblasts. </p>
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<span class="mim-font">
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<strong>.0012 COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 14</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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FARS2, ARG198LEU
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<br />
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ClinVar: RCV003459881
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</div>
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<span class="mim-text-font">
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<p>For discussion of the c.593G-T transversion (c.593G-T, NM_006567.5) in the FARS2 gene that was found in compound heterozygous state in an infant with combined oxidative phosphorylation deficiency-14 (COXPD14; 614946) by Chen et al. (2023), see 611592.0002. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<ol>
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Almalki, A., Alston, C. L., Parker, A., Simonic, I., Mehta, S. G., He, L., Reza, M., Oliveira, J. M. A., Lightowlers, R. N., McFarland, R., Taylor, R. W., Chrzanowska-Lightowlers, Z. M. A.
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<strong>Mutation of the human mitochondrial phenylalanine-tRNA synthetase causes infantile-onset epilepsy and cytochrome c oxidase deficiency.</strong>
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Biochim. Biophys. Acta 1842: 56-64, 2014.
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[PubMed: 24161539]
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[Full Text: https://doi.org/10.1016/j.bbadis.2013.10.008]
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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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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: 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>
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<p class="mim-text-font">
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Bullard, J. M., Cai, Y.-C., Demeler, B., Spremulli, L. L.
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<strong>Expression and characterization of a human mitochondrial phenylalanyl-tRNA synthetase.</strong>
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J. Molec. Biol. 288: 567-577, 1999.
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[PubMed: 10329163]
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[Full Text: https://doi.org/10.1006/jmbi.1999.2708]
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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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Chen, W., Rehsi, P., Thompson, K., Yeo, M., Stals, K., He, L., Schimmel, P., Chrzanowska-Lightowlers, Z. M. A., Wakeling, E., Taylor, R. W., Kuhle, B.
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<strong>Clinical and molecular characterization of novel FARS2 variants causing neonatal mitochondrial disease.</strong>
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Molec. Genet. Metab. 140: 107657, 2023.
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[PubMed: 37523899]
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[Full Text: https://doi.org/10.1016/j.ymgme.2023.107657]
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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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Elo, J. M., Yadavalli, S. S., Euro, L., Isohanni, P., Gotz, A., Carroll, C. J., Valanne, L., Alkuraya, F. S., Uusimaa, J., Paetau, A., Caruso, E. M., Pihko, H., Ibba, M., Tyynismaa, H., Suomalainen, A.
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<strong>Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy.</strong>
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Hum. Molec. Genet. 21: 4521-4529, 2012.
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[PubMed: 22833457]
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[Full Text: https://doi.org/10.1093/hmg/dds294]
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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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Gross, M. B.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 2/1/2018.
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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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Shamseldin, H. E., Alshammari, M., Al-Sheddi, T., Salih, M. A., Alkhalidi, H., Kentab, A., Repetto, G. M., Hashem, M., Alkuraya, F. S.
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<strong>Genomic analysis of mitochondrial diseases in a consanguineous population reveals novel candidate disease genes.</strong>
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J. Med. Genet. 49: 234-241, 2012.
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[PubMed: 22499341]
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[Full Text: https://doi.org/10.1136/jmedgenet-2012-100836]
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<li>
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<p class="mim-text-font">
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Vantroys, E., Larson, A., Friederich, M., Knight, K., Swanson, M. A., Powell, C. A., Smet, J., Vergult, S., De Paepe, B., Seneca, S., Roeyers, H., Menten, B., Minczuk, M., Vanlander, A., Van Hove, J., Van Coster, R.
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<strong>New insights into the phenotype of FARS2 deficiency.</strong>
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Molec. Genet. Metab. 122: 172-181, 2017.
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[PubMed: 29126765]
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[Full Text: https://doi.org/10.1016/j.ymgme.2017.10.004]
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</li>
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<li>
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<p class="mim-text-font">
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Vernon, H. J., McClellan, R., Batista, D. A. S., Naidu, S.
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<strong>Mutations in FARS2 and non-fatal mitochondrial dysfunction in two siblings.</strong>
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Am. J. Med. Genet. 167A: 1147-1151, 2015.
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[PubMed: 25851414]
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[Full Text: https://doi.org/10.1002/ajmg.a.36993]
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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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Yang, Y., Liu, W., Fang, Z., Shi, J., Che, F., He, C., Yao, L., Wang, E., Wu, Y.
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<strong>A newly identified missense mutation in FARS2 causes autosomal-recessive spastic paraplegia.</strong>
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Hum. Mutat. 37: 165-169, 2016.
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[PubMed: 26553276]
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[Full Text: https://doi.org/10.1002/humu.22930]
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Hilary J. Vernon - updated : 12/21/2023<br>Matthew B. Gross - updated : 02/01/2018<br>Ada Hamosh - updated : 01/30/2018<br>Ada Hamosh - updated : 01/29/2018<br>Cassandra L. Kniffin - updated : 07/21/2016<br>Cassandra L. Kniffin - updated : 11/28/2012<br>Patricia A. Hartz - updated : 5/21/2009
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carol : 12/21/2023<br>carol : 12/18/2019<br>mgross : 02/01/2018<br>carol : 01/30/2018<br>carol : 01/29/2018<br>carol : 07/29/2016<br>carol : 07/28/2016<br>ckniffin : 07/21/2016<br>mcolton : 05/12/2015<br>carol : 12/3/2012<br>ckniffin : 11/28/2012<br>mgross : 5/26/2009<br>terry : 5/21/2009<br>wwang : 11/8/2007
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