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<title>
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Entry
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- *601421 - LYSYL-tRNA SYNTHETASE 1; KARS1
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- OMIM
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</ul>
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</nav>
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<div id="mimSearch" class="hidden-print">
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<div class="container">
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<form method="get" action="/search" id="mimEntrySearchForm" name="entrySearchForm" class="form-horizontal">
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchStart" name="start" value="1" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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<input type="hidden" id="mimSearchSort" name="sort" value="score desc, prefix_sort desc" />
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<div class="row">
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<div class="col-lg-8 col-md-8 col-sm-8 col-xs-8">
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<div class="form-group">
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<div class="input-group">
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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<div class="input-group-btn">
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<button type="submit" id="mimEntrySearchSubmit" class="btn btn-default" style="width: 5em;"><span class="glyphicon glyphicon-search"></span></button>
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<button type="button" class="btn btn-default dropdown-toggle" data-toggle="dropdown"> Options <span class="caret"></span></button>
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<ul class="dropdown-menu dropdown-menu-right">
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<li class="dropdown-header">
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Advanced Search
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/entry"> OMIM </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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<li role="separator" class="divider"></li>
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<li>
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<a href="/history"> Search History </a>
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</ul>
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</div>
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<div class="autocomplete" id="mimEntrySearchAutocomplete"></div>
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</form>
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<div class="row">
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<p />
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</div>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-2 hidden-sm hidden-xs">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*601421</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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</li>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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</li>
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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>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
|
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<a href="/allelicVariants/601421">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
|
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<div style="display: table-row">
|
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
|
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</div>
|
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
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</a>
|
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</span>
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</span>
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</div>
|
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
|
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<div class="panel-body small mim-panel-body">
|
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|
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000065427;t=ENST00000302445" 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=3735" 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=601421" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000065427;t=ENST00000302445" 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_001130089,NM_001378148,NM_005548" 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_005548" 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=601421" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
|
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</div>
|
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</div>
|
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</div>
|
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
|
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</a>
|
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</span>
|
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</span>
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</div>
|
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=03249&isoform_id=03249_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/KARS1" 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/2366752,5031815,11095909,13278705,20178333,34533120,119616025,119616026,119616027,119616028,119616029,119616030,194272210,929653757,1802983340" 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/Q15046" 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=3735" 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=ENSG00000065427;t=ENST00000302445" 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=KARS1" 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=KARS1" 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+3735" 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/KARS1" 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:3735" 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/3735" 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=chr16&hgg_gene=ENST00000302445.8&hgg_start=75627724&hgg_end=75647665&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:6215" 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:6215" 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=601421[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=601421[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/KARS1/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/ENSG00000065427" 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=KARS1" 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=KARS1" 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=KARS1" 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=KARS1&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/PA30016" 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:6215" 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/FBgn0027084.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:1934754" 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/KARS1#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:1934754" 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/3735/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=3735" 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=WBGene00002238;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-021115-8" 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:3735" 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=KARS1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
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601421
|
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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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LYSYL-tRNA SYNTHETASE 1; KARS1
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</span>
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</h3>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
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KARS<br />
|
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KRS
|
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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=KARS1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">KARS1</a></em></strong>
|
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</span>
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/16/655?start=-3&limit=10&highlight=655">16q23.1</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr16:75627724-75647665&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'})">16:75,627,724-75,647,665</a> </span>
|
|
</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>
|
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<br />
|
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
|
<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">
|
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<thead>
|
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<tr class="active">
|
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<th>
|
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Location
|
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</th>
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<th>
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Phenotype
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?Charcot-Marie-Tooth disease, recessive intermediate, B
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Deafness, autosomal recessive 89
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Leukoencephalopathy, progressive, infantile-onset, with or without deafness
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>The KARS gene encodes lysyl-tRNA synthetase, which catalyzes the aminoacylation of tRNA-lys in both the cytoplasm and mitochondria. Protein synthesis is initiated by the attachment of amino acids to cognate tRNAs by aminoacyl-tRNA synthetases (ARSs). At least 6 of 20 human ARSs, including KARS, had been identified as targets of autoantibodies in the autoimmune disease polymyositis/dermatomyositis (<a href="#17" class="mim-tip-reference" title="Targoff, I. N., Trieu, E. P., Miller, F. W. <strong>Reaction of anti-OJ autoantibodies with components of the multi-enzyme complex of aminoacyl-tRNA synthetases in addition to isoleucyl-tRNA synthetase.</strong> J. Clin. Invest. 91: 2556-2564, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8514867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8514867</a>] [<a href="https://doi.org/10.1172/JCI116493" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8514867">Targoff et al. (1993)</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8514867" 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="#18" class="mim-tip-reference" title="Tolkunova, E., Park, H., Xia, J., King, M. P., Davidson, E. <strong>The human lysyl-tRNA synthetase gene encodes both the cytoplasmic and mitochondrial enzymes by means of an unusual alternative splicing of the primary transcript.</strong> J. Biol. Chem. 275: 35063-35069, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10952987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10952987</a>] [<a href="https://doi.org/10.1074/jbc.M006265200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10952987">Tolkunova et al. (2000)</a> identified 2 full-length sequences for KARS and determined that they represent cytoplasmic and mitochondrial isoforms. The 625-amino acid mitochondrial enzyme and the 597-amino acid cytoplasmic enzyme are identical over the last 576 amino acids, but the mitochondrial enzyme has a different 49-amino acid N terminus containing a mitochondrial targeting sequence. Transfection of both fluorescence-tagged isoforms into an osteosarcoma cell line showed that the cytoplasmic isoform produced a diffuse, cellwide fluorescence, while the mitochondrial isoform resulted in a punctate pattern that colocalized with mitochondrial markers. Ribonuclease protection analysis indicated that the mRNA encoding the cytoplasmic isoform makes up approximately 70%, and the mitochondrial isoform approximately 30%, of mature KARS transcripts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10952987" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using massively parallel sequencing and RT-PCR experiments, <a href="#15" class="mim-tip-reference" title="Santos-Cortez, R. L. P., Lee, K., Azeem, Z., Antonellis, P. J., Pollock, L. M., Khan, S., Irfanullah, Andrade-Elizondo, P. B., Chiu, I., Adams, M. D., Basit, S., Smith, J. D., University of Washington Center for Mendelian Genomics, Nickerson, D. A., McDermott, B. M., Jr., Ahmad, W., Leal, S. M. <strong>Mutations in KARS, encoding lysyl-tRNA synthetase, cause autosomal-recessive nonsyndromic hearing impairment DFNB89.</strong> Am. J. Hum. Genet. 93: 132-140, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23768514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23768514</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23768514[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.05.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23768514">Santos-Cortez et al. (2013)</a> demonstrated that KARS is expressed in hair cells of zebrafish, chickens, and mice, as well as in maculae of zebrafish and mice. Immunolabeling experiments using mouse vestibular tissue revealed broad distribution of KARS in hair cells and supporting cells, and organ of Corti sections showed KARS localization to inner and outer hair cells, Dieter cells, and basilar membrane. In addition, the tectorial membrane showed a strong affinity for KARS antibody, and KARS labeling was strongest within the spiral ligament, particularly in the area containing type II and type IV fibrocytes. KARS was also strongly localized to the outer and inner sulcus cells and spiral limbus epithelium. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23768514" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Lo, W.-S., Gardiner, E., Xu, Z., Lau, C.-F., Wang, F., Zhou, J. J., Mendlein, J. D., Nangle, L. A., Chiang, K. P., Yang, X.-L., Au, K.-F., Wong, W. H., Guo, M., Zhang, M., Schimmel, P. <strong>Human tRNA synthetase catalytic nulls with diverse functions.</strong> Science 345: 328-332, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25035493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25035493</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25035493[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1252943" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25035493">Lo et al. (2014)</a> reported the discovery of a large number of natural catalytic nulls for each human aminoacyl tRNA synthetase. Splicing events retain noncatalytic domains while ablating the catalytic domain to create catalytic nulls with diverse functions. Each synthetase is converted into several new signaling proteins with biologic activities 'orthogonal' to that of the catalytic parent. The recombinant aminoacyl tRNA synthetase variants had specific biologic activities across a spectrum of cell-based assays: about 46% across all species affect transcriptional regulation, 22% cell differentiation, 10% immunomodulation, 10% cytoprotection, and 4% each for proliferation, adipogenesis/cholesterol transport, and inflammatory response. <a href="#7" class="mim-tip-reference" title="Lo, W.-S., Gardiner, E., Xu, Z., Lau, C.-F., Wang, F., Zhou, J. J., Mendlein, J. D., Nangle, L. A., Chiang, K. P., Yang, X.-L., Au, K.-F., Wong, W. H., Guo, M., Zhang, M., Schimmel, P. <strong>Human tRNA synthetase catalytic nulls with diverse functions.</strong> Science 345: 328-332, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25035493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25035493</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25035493[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1252943" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25035493">Lo et al. (2014)</a> identified in-frame splice variants of cytoplasmic aminoacyl tRNA synthetases. They identified 3 catalytic-null splice variants for cytoplasmic LysRS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25035493" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The KARS1 gene encodes both the cytosolic and mitochondrial isoforms of KARS1, which are generated by alternative splicing. The cytoplasmic isoform skips exon 2 and splices exon 1 to exon 3, whereas the mitochondrial isoform includes exon 2. The ATG initiation codons are different between the 2 isoforms. The mitochondrial isoform has 28 more residues than the cytosolic isoform. The cytoplasmic isoform represents about 70% and the mitochondrial isoform about 30% of the mature transcript from the KARS1 gene (summary by <a href="#16" class="mim-tip-reference" title="Scheidecker, S., Bar, S., Stoetzel, C., Geoffroy, V., Lannes, B., Rinaldi, B., Fischer, F., Becker, H. D., Pelletier, V., Pagan, C., Acquaviva-Bourdain, C., Kremer, S., Mirande, M., Tranchant, C., Muller, J., Friant, S., Dollfus, H. <strong>Mutations in KARS cause a severe neurological and neurosensory disease with optic neuropathy.</strong> Hum. Mutat. 40: 1826-1840, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31116475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31116475</a>] [<a href="https://doi.org/10.1002/humu.23799" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31116475">Scheidecker et al., 2019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31116475" 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="#18" class="mim-tip-reference" title="Tolkunova, E., Park, H., Xia, J., King, M. P., Davidson, E. <strong>The human lysyl-tRNA synthetase gene encodes both the cytoplasmic and mitochondrial enzymes by means of an unusual alternative splicing of the primary transcript.</strong> J. Biol. Chem. 275: 35063-35069, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10952987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10952987</a>] [<a href="https://doi.org/10.1074/jbc.M006265200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10952987">Tolkunova et al. (2000)</a> determined that the KARS gene contains 15 exons and spans about 20 kb. The cytoplasmic and mitochondrial KARS isoforms result from alternative splicing of the first 3 exons. <a href="#18" class="mim-tip-reference" title="Tolkunova, E., Park, H., Xia, J., King, M. P., Davidson, E. <strong>The human lysyl-tRNA synthetase gene encodes both the cytoplasmic and mitochondrial enzymes by means of an unusual alternative splicing of the primary transcript.</strong> J. Biol. Chem. 275: 35063-35069, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10952987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10952987</a>] [<a href="https://doi.org/10.1074/jbc.M006265200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10952987">Tolkunova et al. (2000)</a> found that the initiation codons for KARS and RAP1 (<a href="/entry/605061">605061</a>) are separated by 243 bp. This region lacks a conventional TATA sequence but contains several SP1 (<a href="/entry/189906">189906</a>)-binding domains oriented in both directions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10952987" 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="#11" class="mim-tip-reference" title="Nichols, R. C., Blinder, J., Pai, S. I., Ge, Q., Targoff, I. N., Plotz, P. H., Liu, P. <strong>Assignment of two human autoantigen genes: isoleucyl-tRNA synthetase locates to 9q21 and lysyl-tRNA synthetase locates to 16q23-q24.</strong> Genomics 36: 210-213, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8812440/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8812440</a>] [<a href="https://doi.org/10.1006/geno.1996.0449" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8812440">Nichols et al. (1996)</a> used Southern hybridization of human/rodent somatic cell hybrids to localize the KARS gene to chromosome 16. By fluorescence in situ hybridization analysis, they assigned the gene to 16q23-q24. By radiation hybrid panel analysis, <a href="#8" class="mim-tip-reference" title="Maas, S., Kim, Y.-G., Rich, A. <strong>Genomic clustering of tRNA-specific adenosine deaminase ADAT1 and two tRNA synthetases.</strong> Mammalian Genome 12: 387-393, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11331948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11331948</a>] [<a href="https://doi.org/10.1007/s003350020008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11331948">Maas et al. (2001)</a> mapped KARS and the gene for tRNA-specific adenosine deaminase (ADAT1; <a href="/entry/604230">604230</a>) to 16q22.2-q22.3, with alanyl-tRNA synthetase (AARS; <a href="/entry/601065">601065</a>) positioned centromeric to these 2 genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11331948+8812440" 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="#18" class="mim-tip-reference" title="Tolkunova, E., Park, H., Xia, J., King, M. P., Davidson, E. <strong>The human lysyl-tRNA synthetase gene encodes both the cytoplasmic and mitochondrial enzymes by means of an unusual alternative splicing of the primary transcript.</strong> J. Biol. Chem. 275: 35063-35069, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10952987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10952987</a>] [<a href="https://doi.org/10.1074/jbc.M006265200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10952987">Tolkunova et al. (2000)</a> found that both full-length mitochondrial and cytoplasmic KARS, purified after expression in E. coli, aminoacylated in vitro transcripts corresponding to both the cytoplasmic and mitochondrial tRNA-lys. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10952987" 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="#13" class="mim-tip-reference" title="Park, S. G., Kim, H. J., Min, Y. H., Choi, E.-C., Shin, Y. K., Park, B.-J., Lee, S. W., Kim, S. <strong>Human lysyl-tRNA synthetase is secreted to trigger proinflammatory response.</strong> Proc. Nat. Acad. Sci. 102: 6356-6361, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15851690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15851690</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15851690[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/10.1073/pnas.0500226102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15851690">Park et al. (2005)</a> stated that, in addition to their essential role in protein synthesis, ARSs function as regulators and signaling molecules. KARS can synthesize diadenosine polyphosphates, and this activity plays a role in transcriptional control through MITF (<a href="/entry/156845">156845</a>). <a href="#13" class="mim-tip-reference" title="Park, S. G., Kim, H. J., Min, Y. H., Choi, E.-C., Shin, Y. K., Park, B.-J., Lee, S. W., Kim, S. <strong>Human lysyl-tRNA synthetase is secreted to trigger proinflammatory response.</strong> Proc. Nat. Acad. Sci. 102: 6356-6361, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15851690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15851690</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15851690[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/10.1073/pnas.0500226102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15851690">Park et al. (2005)</a> found that KARS was secreted from multiple human cell lines in response to TNF-alpha (TNF; <a href="/entry/191160">191160</a>). Secreted KARS bound macrophages and peripheral blood mononuclear cells and enhanced TNF-alpha production and cell migration. The signaling pathways triggered by KARS involved ERK (see MAPK3; <a href="/entry/601795">601795</a>), p38 MAPK (MAPK14; <a href="/entry/600289">600289</a>), and an inhibitory G protein (see GNAI1, <a href="/entry/139310">139310</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15851690" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Charcot-Marie-Tooth Disease, Recessive Intermediate B</em></strong></p><p>
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<a href="#9" class="mim-tip-reference" title="McLaughlin, H. M., Sakaguchi, R., Liu, C., Igarashi, T., Pehlivan, D., Chu, K., Iyer, R., Cruz, P., Cherukuri, P. F., Hansen, N. F., Mullikin, J.C., NISC Comparative Sequencing Program, and 13 others. <strong>Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy.</strong> Am. J. Hum. Genet. 87: 560-566, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20920668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20920668</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20920668[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.09.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20920668">McLaughlin et al. (2010)</a> noted that mutations in 3 genes encoding aminoacyl-tRNA synthetases, GARS (<a href="/entry/600287">600287</a>), YARS (<a href="/entry/603623">603623</a>), and AARS (<a href="/entry/601065">601065</a>), had been implicated in Charcot-Marie-Tooth (CMT) disease primarily associated with an axonal pathology (CMT2D, <a href="/entry/601472">601472</a>; CMTDIC, <a href="/entry/608323">608323</a>; and CMT2N, <a href="/entry/613287">613287</a>, respectively). They performed a large-scale mutation screen of 37 human ARS genes in a cohort of 355 patients with a phenotype consistent with CMT. One patient was found to be compound heterozygous for 2 mutations in the KARS gene (<a href="#0001">601421.0001</a> and <a href="#0002">601421.0002</a>). The phenotype was consistent with a recessive intermediate form of CMT (CMTRIB; <a href="/entry/613641">613641</a>), but the patient had additional features, including developmental delay, dysmorphic features, and vestibular Schwannoma. Because the patient was adopted, parental studies were not possible. Thus, KARS was the fourth ARS gene associated with CMT disease, indicating that this family of enzymes is specifically critical for axon function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20920668" 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 Deafness 89</em></strong></p><p>
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In affected individuals from 3 consanguineous Pakistani families with nonsyndromic deafness mapping to chromosome 16q21-q23.2, (DFNB89; <a href="/entry/613916">613916</a>), <a href="#15" class="mim-tip-reference" title="Santos-Cortez, R. L. P., Lee, K., Azeem, Z., Antonellis, P. J., Pollock, L. M., Khan, S., Irfanullah, Andrade-Elizondo, P. B., Chiu, I., Adams, M. D., Basit, S., Smith, J. D., University of Washington Center for Mendelian Genomics, Nickerson, D. A., McDermott, B. M., Jr., Ahmad, W., Leal, S. M. <strong>Mutations in KARS, encoding lysyl-tRNA synthetase, cause autosomal-recessive nonsyndromic hearing impairment DFNB89.</strong> Am. J. Hum. Genet. 93: 132-140, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23768514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23768514</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23768514[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.05.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23768514">Santos-Cortez et al. (2013)</a> identified homozygosity for 2 missense mutations in the KARS gene, Y173H (<a href="#0003">601421.0003</a>) and D377N (<a href="#0004">601421.0004</a>), that segregated with disease in the respective families and were not found in ethnically matched controls or in variant databases. Additional testing for evaluation of CMT disease and acoustic neuroma in 3 affected members from 2 of the DFNB89 families showed no evidence of auditory or limb neuropathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23768514" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Infantile-Onset Progressive Leukoencephalopathy with or without Deafness</em></strong></p><p>
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In 2 sibs, born of unrelated parents, with infantile-onset progressive leukoencephalopathy without deafness (LEPID; <a href="/entry/619147">619147</a>), <a href="#10" class="mim-tip-reference" title="McMillan, H. J., Humphreys, P., Smith, A., Schwartzentruber, J., Chakraborty, P., Bulman, D. E., Beaulieu, C. L., FORGE Canada Consortium, Majewski, J., Boycott, K. M., Geraghty, M. T. <strong>Congenital visual impairment and progressive microcephaly due to lysyl-transfer ribonucleic acid (RNA) synthetase (KARS) mutations: the expanding phenotype of aminoacyl-transfer RNA synthetase mutations in human disease.</strong> J. Child Neurol. 30: 1037-1043, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25330800/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25330800</a>] [<a href="https://doi.org/10.1177/0883073814553272" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25330800">McMillan et al. (2015)</a> identified compound heterozygous missense in the KARS1 gene (R438W, <a href="#0005">601421.0005</a> and E525K, <a href="#0006">601421.0006</a>). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed, but both mutations occurred in a highly conserved region of the catalytic domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25330800" 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 (patient 459) with deficiencies of mitochondrial complexes I and IV, <a href="#5" class="mim-tip-reference" title="Kohda, M., Tokuzawa, Y., Kishita, Y., Nyuzuki, H., Moriyama, Y., Mizuno, Y., Hirata, T., Yatsuka, Y., Yamashita-Sugahara, Y., Nakachi, Y., Kato, H., Okuda, A., and 23 others. <strong>A comprehensive genomic analysis reveals the genetic landscape of mitochondrial respiratory chain complex deficiencies.</strong> PLoS Genet. 12: e1005679, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26741492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26741492</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26741492[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/10.1371/journal.pgen.1005679" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26741492">Kohda et al. (2016)</a> identified compound heterozygous missense mutations in the KARS1 gene: a c.1343T-A transversion (NM_005548), resulting in a val448-to-asp (V448D) substitution, and a c.953T-C transition, resulting in an ile318-to-thr (I318T) substitution. The mutations, which were found by high-throughput exome sequencing of 142 unrelated patients with childhood-onset mitochondrial respiratory chain complex deficiencies, segregated with the disorder in the family. A cDNA complementation assay revealed that mitochondrial KARS, but not the cytosolic form, successfully rescued the enzyme defects and assembly of complexes I and IV. Clinical details of the patient were limited, but he was noted to have developmental delay, seizures, nystagmus, lactic acidosis, and hypertrophic cardiomyopathy, suggestive of LEPID. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26741492" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 unrelated patients with LEPID, <a href="#1" class="mim-tip-reference" title="Ardissone, A., Tonduti, D., Legati, A., Lamantea, E., Barone, R., Dorboz, I., Boespflug-Tanguy, O., Nebbia, G., Maggioni, M., Garavaglia, B., Moroni, I., Farina, L., Pichiecchio, A., Orcesi, S., Chiapparini, L., Ghezzi, D. <strong>KARS-related diseases: progressive leukoencephalopathy with brainstem and spinal cord calcifications as new phenotype and a review of literature.</strong> Orphanet J. Rare Dis. 13: 45, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29615062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29615062</a>] [<a href="https://doi.org/10.1186/s13023-018-0788-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29615062">Ardissone et al. (2018)</a> identified homozygous or compound heterozygous missense mutations in the KARS1 gene (see, e.g., <a href="#0007">601421.0007</a>). The mutations, which were found by whole-exome or next-generation sequencing of a panel, were confirmed by Sanger sequencing and demonstrated to segregate with the disorder in at least 1 family. Functional studies of the variants and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29615062" 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 French girl with LEPID, <a href="#14" class="mim-tip-reference" title="Ruzzenente, B., Assouline, Z., Barcia, G., Rio, M., Boddaert, N., Munnich, A., Rotig, A., Metodiev, M. D. <strong>Inhibition of mitochondrial translation in fibroblasts from a patient expressing the KARS p.(pro228leu) variant and presenting with sensorineural deafness, developmental delay, and lactic acidosis.</strong> Hum. Mutat. 39: 2047-2059, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30252186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30252186</a>] [<a href="https://doi.org/10.1002/humu.23657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30252186">Ruzzenente et al. (2018)</a> identified compound heterozygous mutations in the KARS1 gene (P228L, <a href="#0009">601421.0009</a> and c.1438delC, <a href="#0010">601421.0010</a>). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Detailed in vitro functional expression studies of patient fibroblasts showed that cytoplasmic translation was intact, but mitochondrial translation was specifically decreased. There were assembly defects of multiple OXPHOS complexes, which could be rescued by expression of mitochondrial KARS1, but not cytoplasmic KARS1. <a href="#14" class="mim-tip-reference" title="Ruzzenente, B., Assouline, Z., Barcia, G., Rio, M., Boddaert, N., Munnich, A., Rotig, A., Metodiev, M. D. <strong>Inhibition of mitochondrial translation in fibroblasts from a patient expressing the KARS p.(pro228leu) variant and presenting with sensorineural deafness, developmental delay, and lactic acidosis.</strong> Hum. Mutat. 39: 2047-2059, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30252186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30252186</a>] [<a href="https://doi.org/10.1002/humu.23657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30252186">Ruzzenente et al. (2018)</a> concluded that inhibition of mitochondrial translation underlies the disease mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30252186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 7 children from 5 unrelated Japanese families with LEPID, <a href="#4" class="mim-tip-reference" title="Itoh, M., Dai, H., Horike, S., Gonzalez, J., Kitami, Y., Meguro-Horike, M., Kuki, I., Shimakawa, S., Yoshinaga, H., Ota, Y., Okazaki, T., Maegaki, Y., Nabatame, S., Okazaki, S., Kawawaki, H., Ueno, N., Goto, Y., Kato, Y. <strong>Biallelic KARS pathogenic variants cause an early-onset progressive leukodystrophy.</strong> Brain 142: 560-573, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30715177/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30715177</a>] [<a href="https://doi.org/10.1093/brain/awz001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30715177">Itoh et al. (2019)</a> identified homozygous or compound heterozygous mutations in the KARS1 gene (see, e.g., <a href="#0012">601421.0012</a> and <a href="#0013">601421.0013</a>). The mutations were found by exome sequencing and confirmed by Sanger sequencing; segregation was consistent with autosomal recessive inheritance in the 2 families from whom parental DNA was available. KARS1 expression levels were decreased in patient tissue, including liver and brain, and enzymatic activity of both the mitochondrial and cytosolic isoforms was decreased compared to controls. Kars-depleted Xenopus embryos showed developmental defects of the head and eyes, which could be rescued with wildtype KARS, but not by the mutant KARS variants found in the patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30715177" 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>Congenital Deafness and Adult-Onset Progressive Leukoencephalopathy</em></strong></p><p>
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In 2 adult sibs, born of unrelated Chinese Han parents, with congenital deafness and adult-onset progressive leukoencephalopathy (DEAPLE; <a href="/entry/619196">619196</a>), <a href="#22" class="mim-tip-reference" title="Zhou, X.-L., He, L.-X., Yu, L.-J., Wang, Y., Wang, X.-J., Wang, E.-D., Yang, T. <strong>Mutations in KARS cause early-onset hearing loss and leukoencephalopathy: potential pathogenic mechanism.</strong> Hum. Mutat. 38: 1740-1750, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28887846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28887846</a>] [<a href="https://doi.org/10.1002/humu.23335" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28887846">Zhou et al. (2017)</a> identified compound heterozygous missense mutations in the KARS1 gene (R477H, <a href="#0007">601421.0007</a> and P505S, <a href="#0008">601421.0008</a>). These mutations correspond to R505H and P533S, respectively, in the mitochondrial isoform (see <a href="#16" class="mim-tip-reference" title="Scheidecker, S., Bar, S., Stoetzel, C., Geoffroy, V., Lannes, B., Rinaldi, B., Fischer, F., Becker, H. D., Pelletier, V., Pagan, C., Acquaviva-Bourdain, C., Kremer, S., Mirande, M., Tranchant, C., Muller, J., Friant, S., Dollfus, H. <strong>Mutations in KARS cause a severe neurological and neurosensory disease with optic neuropathy.</strong> Hum. Mutat. 40: 1826-1840, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31116475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31116475</a>] [<a href="https://doi.org/10.1002/humu.23799" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31116475">Scheidecker et al., 2019</a>). The mutations, which were found by next-generation sequencing of candidate genes and confirmed by Sanger sequencing, segregated with the disorder in the family. Both mutations affected highly conserved residues in the catalytic domain. In vitro functional expression studies showed that the R477H mutation impaired KARS incorporation into the multiple-synthetase complex (MSC). In addition, both mutations caused abnormal protein aggregation and resulted in decreased KARS aminoacylation activity (5.7% that of wildtype for the combined mutations). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=28887846+31116475" 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 36-year-old man (patient 5) with DEAPLE, <a href="#19" class="mim-tip-reference" title="van der Knaap, M. S., Bugiani, M., Mendes, M. I., Riley, L. G., Smith, D. E. C., Rudinger-Thirion, J., Frugier, M., Breur, M., Crawford, J., van Gaalen, J., Schouten, M., Willems, M., and 10 others. <strong>Biallelic variants in LARS2 and KARS cause deafness and (ovario)leukodystrophy.</strong> Neurology 92: e1225-e1237, 2019. Note: Electronic Article. Erratum: Neurology 93: 982 only, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30737337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30737337</a>] [<a href="https://doi.org/10.1212/WNL.0000000000007098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30737337">van der Knaap et al. (2019)</a> identified compound heterozygous missense mutations in the KARS gene (R108H and V476F). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Patient-derived fibroblasts showed about a 50% decrease in cytosolic KARS aminoacylation activity compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30737337" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a French woman with DEAPLE, <a href="#16" class="mim-tip-reference" title="Scheidecker, S., Bar, S., Stoetzel, C., Geoffroy, V., Lannes, B., Rinaldi, B., Fischer, F., Becker, H. D., Pelletier, V., Pagan, C., Acquaviva-Bourdain, C., Kremer, S., Mirande, M., Tranchant, C., Muller, J., Friant, S., Dollfus, H. <strong>Mutations in KARS cause a severe neurological and neurosensory disease with optic neuropathy.</strong> Hum. Mutat. 40: 1826-1840, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31116475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31116475</a>] [<a href="https://doi.org/10.1002/humu.23799" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31116475">Scheidecker et al. (2019)</a> identified compound heterozygous missense mutations in the KARS1 gene (P228L, <a href="#0009">601421.0009</a> and F291V, <a href="#0011">601421.0011</a>). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The P228L and F291V mutations correspond to P200L and F263V in the cytoplasmic isoform. Analysis of patient cells showed increased levels of mitochondrial KARS compared to cytoplasmic KARS, the latter of which showed decreased stability. In vitro immunoprecipitation studies in a yeast 2-hybrid assay showed that the cytoplasmic P200L and F263V mutants had reduced binding to p38 (AIMP2; <a href="/entry/600859">600859</a>). The authors suggested that these mutations may be pathogenic by impairing the association of cytoplasmic KARS with the MSC complex, thus adversely affecting cytoplasmic protein synthesis. These variants also had decreased aminoacylation activity compared to wildtype KARS. Patient skeletal muscle showed decreased activities of mitochondrial complexes I and IV, and there was an overexpression of KARS in the mitochondria, suggesting mitochondrial dysfunction. <a href="#16" class="mim-tip-reference" title="Scheidecker, S., Bar, S., Stoetzel, C., Geoffroy, V., Lannes, B., Rinaldi, B., Fischer, F., Becker, H. D., Pelletier, V., Pagan, C., Acquaviva-Bourdain, C., Kremer, S., Mirande, M., Tranchant, C., Muller, J., Friant, S., Dollfus, H. <strong>Mutations in KARS cause a severe neurological and neurosensory disease with optic neuropathy.</strong> Hum. Mutat. 40: 1826-1840, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31116475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31116475</a>] [<a href="https://doi.org/10.1002/humu.23799" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31116475">Scheidecker et al. (2019)</a> hypothesized that the mitochondrial dysfunction was secondary to defects in cytoplasmic KARS protein synthesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31116475" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), <a href="#3" class="mim-tip-reference" title="Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. <strong>High-throughput discovery of novel developmental phenotypes.</strong> Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27626380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27626380</a>] [<a href="https://doi.org/10.1038/nature19356" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27626380">Dickinson et al. (2016)</a> found that knockout of the mouse homolog of human KARS is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27626380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a patient with an intermediate form of autosomal recessive Charcot-Marie-Tooth disease (CMTRIB; <a href="/entry/613641">613641</a>), <a href="#9" class="mim-tip-reference" title="McLaughlin, H. M., Sakaguchi, R., Liu, C., Igarashi, T., Pehlivan, D., Chu, K., Iyer, R., Cruz, P., Cherukuri, P. F., Hansen, N. F., Mullikin, J.C., NISC Comparative Sequencing Program, and 13 others. <strong>Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy.</strong> Am. J. Hum. Genet. 87: 560-566, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20920668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20920668</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20920668[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.09.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20920668">McLaughlin et al. (2010)</a> identified compound heterozygosity for 2 mutations in the KARS gene: a 398T-A transversion resulting in a leu133-to-his (L133H) substitution in a highly conserved residue, and a 2-bp insertion (524insTT; <a href="#0002">601421.0002</a>) predicted to result in a frameshift, premature termination, and a null allele, as confirmed in yeast complementation studies. The L133H substitution occurred in an N-terminal anticodon-binding domain adjacent to the dimer-dimer interface. In vitro functional expression assays showed that the L133H mutant had severely impaired enzyme activity, with a 94% loss of catalytic activity compared to wildtype. In addition to peripheral neuropathy, the patient also had developmental delay, self-abusive behavior, dysmorphic features, and vestibular Schwannoma, which <a href="#9" class="mim-tip-reference" title="McLaughlin, H. M., Sakaguchi, R., Liu, C., Igarashi, T., Pehlivan, D., Chu, K., Iyer, R., Cruz, P., Cherukuri, P. F., Hansen, N. F., Mullikin, J.C., NISC Comparative Sequencing Program, and 13 others. <strong>Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy.</strong> Am. J. Hum. Genet. 87: 560-566, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20920668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20920668</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20920668[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.09.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20920668">McLaughlin et al. (2010)</a> postulated was due to severe loss of KARS function in both the cytoplasm and mitochondria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20920668" 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>For discussion of the 2-bp insertion in the KARS gene (524insTT) that was found in compound heterozygous state in a patient with an intermediate form of autosomal recessive Charcot-Marie-Tooth disease (CMTRIB; <a href="/entry/613641">613641</a>) by <a href="#9" class="mim-tip-reference" title="McLaughlin, H. M., Sakaguchi, R., Liu, C., Igarashi, T., Pehlivan, D., Chu, K., Iyer, R., Cruz, P., Cherukuri, P. F., Hansen, N. F., Mullikin, J.C., NISC Comparative Sequencing Program, and 13 others. <strong>Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy.</strong> Am. J. Hum. Genet. 87: 560-566, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20920668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20920668</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20920668[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.09.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20920668">McLaughlin et al. (2010)</a>, see <a href="#0001">601421.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20920668" 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> rs397514745 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514745;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/rs397514745?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=rs397514745" 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=rs397514745" 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=RCV000054525 OR RCV000627042 OR RCV001807772" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000054525, RCV000627042, RCV001807772" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000054525...</a>
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<p>In affected individuals from 2 consanguineous Pakistani families with nonsyndromic deafness (DFNB89; <a href="/entry/613916">613916</a>), 1 of which (family 4406) had previously been studied by <a href="#2" class="mim-tip-reference" title="Basit, S., Lee, K., Habib, R., Chen, L., Kalsoom, U., Santos-Cortez, R. L. P., Azeem, Z., Andrade, P., Ansar, M., Ahmad, W., Leal, S. M. <strong>DFNB89, a novel autosomal recessive nonsyndromic hearing impairment locus on chromosome 16q21-q23.2.</strong> Hum. Genet. 129: 379-285, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21181198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21181198</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21181198[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s00439-010-0934-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21181198">Basit et al. (2011)</a>, <a href="#15" class="mim-tip-reference" title="Santos-Cortez, R. L. P., Lee, K., Azeem, Z., Antonellis, P. J., Pollock, L. M., Khan, S., Irfanullah, Andrade-Elizondo, P. B., Chiu, I., Adams, M. D., Basit, S., Smith, J. D., University of Washington Center for Mendelian Genomics, Nickerson, D. A., McDermott, B. M., Jr., Ahmad, W., Leal, S. M. <strong>Mutations in KARS, encoding lysyl-tRNA synthetase, cause autosomal-recessive nonsyndromic hearing impairment DFNB89.</strong> Am. J. Hum. Genet. 93: 132-140, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23768514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23768514</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23768514[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.05.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23768514">Santos-Cortez et al. (2013)</a> identified homozygosity for a c.517T-C transition in exon 5 of the KARS gene, resulting in a tyr173-to-his (Y173H) substitution at a highly conserved residue within the beta-2 strand. The mutation segregated with disease in both families and was not found in 325 ethnically matched controls or in variant databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21181198+23768514" 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 DEAFNESS, AUTOSOMAL RECESSIVE 89</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> rs397514746 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514746;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/rs397514746?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=rs397514746" 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=rs397514746" 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=RCV000054526 OR RCV001775565" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000054526, RCV001775565" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000054526...</a>
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<p>In an affected individual from a consanguineous Pakistani family with nonsyndromic deafness (DFNB89; <a href="/entry/613916">613916</a>), previously studied by <a href="#2" class="mim-tip-reference" title="Basit, S., Lee, K., Habib, R., Chen, L., Kalsoom, U., Santos-Cortez, R. L. P., Azeem, Z., Andrade, P., Ansar, M., Ahmad, W., Leal, S. M. <strong>DFNB89, a novel autosomal recessive nonsyndromic hearing impairment locus on chromosome 16q21-q23.2.</strong> Hum. Genet. 129: 379-285, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21181198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21181198</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21181198[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s00439-010-0934-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21181198">Basit et al. (2011)</a> (family 4338), <a href="#15" class="mim-tip-reference" title="Santos-Cortez, R. L. P., Lee, K., Azeem, Z., Antonellis, P. J., Pollock, L. M., Khan, S., Irfanullah, Andrade-Elizondo, P. B., Chiu, I., Adams, M. D., Basit, S., Smith, J. D., University of Washington Center for Mendelian Genomics, Nickerson, D. A., McDermott, B. M., Jr., Ahmad, W., Leal, S. M. <strong>Mutations in KARS, encoding lysyl-tRNA synthetase, cause autosomal-recessive nonsyndromic hearing impairment DFNB89.</strong> Am. J. Hum. Genet. 93: 132-140, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23768514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23768514</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23768514[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.05.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23768514">Santos-Cortez et al. (2013)</a> identified homozygosity for a c.1129G-A transition in exon 9 of the KARS gene, resulting in an asp377-to-asn (D377N) substitution at a completely conserved residue within alpha-helix 9, predicted to affect the configuration of the tetramer interface. The mutation segregated with disease in the family and was not found in 325 ethnically matched controls or in variant databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21181198+23768514" 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 LEUKOENCEPHALOPATHY, PROGRESSIVE, INFANTILE-ONSET, WITHOUT DEAFNESS</strong>
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KARS1, ARG438TRP
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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> rs761527468 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs761527468;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/rs761527468?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=rs761527468" 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=rs761527468" 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=RCV001293656 OR RCV004531073" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001293656, RCV004531073" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001293656...</a>
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<p>In 2 sibs, born of unrelated parents, with infantile-onset progressive leukoencephalopathy without deafness (LEPID; <a href="/entry/619147">619147</a>), <a href="#10" class="mim-tip-reference" title="McMillan, H. J., Humphreys, P., Smith, A., Schwartzentruber, J., Chakraborty, P., Bulman, D. E., Beaulieu, C. L., FORGE Canada Consortium, Majewski, J., Boycott, K. M., Geraghty, M. T. <strong>Congenital visual impairment and progressive microcephaly due to lysyl-transfer ribonucleic acid (RNA) synthetase (KARS) mutations: the expanding phenotype of aminoacyl-transfer RNA synthetase mutations in human disease.</strong> J. Child Neurol. 30: 1037-1043, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25330800/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25330800</a>] [<a href="https://doi.org/10.1177/0883073814553272" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25330800">McMillan et al. (2015)</a> identified compound heterozygous missense mutations in the KARS1 gene: a c.1312C-T transition (c.1312C-T, NM_005548.2), resulting in an arg438-to-trp (R438W) substitution, and a c.1573G-A transition, resulting in a glu525-to-lys (E525K; <a href="#0006">601421.0006</a>) substitution. Both mutations occurred at a highly conserved region of the catalytic domain. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed. The patients presented in infancy with visual impairment, progressive microcephaly, and global developmental delay with poor language acquisition. They also had seizures that could be controlled with medication. Neither was deaf. Brain imaging showed subcortical white matter abnormalities with delayed myelination and thin corpus callosum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25330800" 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 LEUKOENCEPHALOPATHY, PROGRESSIVE, INFANTILE-ONSET, WITHOUT DEAFNESS</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> rs770522582 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs770522582;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/rs770522582?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=rs770522582" 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=rs770522582" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001293657" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001293657" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001293657</a>
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<p>For discussion of the c.1573G-A transition (c.1573G-A, NM_005548.2) in the KARS1 gene, resulting in a glu525-to-lys (E525K) substitution, that was found in compound heterozygous state in 2 sibs with infantile-onset progressive leukoencephalopathy without deafness (LEPID; <a href="/entry/619147">619147</a>) by <a href="#10" class="mim-tip-reference" title="McMillan, H. J., Humphreys, P., Smith, A., Schwartzentruber, J., Chakraborty, P., Bulman, D. E., Beaulieu, C. L., FORGE Canada Consortium, Majewski, J., Boycott, K. M., Geraghty, M. T. <strong>Congenital visual impairment and progressive microcephaly due to lysyl-transfer ribonucleic acid (RNA) synthetase (KARS) mutations: the expanding phenotype of aminoacyl-transfer RNA synthetase mutations in human disease.</strong> J. Child Neurol. 30: 1037-1043, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25330800/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25330800</a>] [<a href="https://doi.org/10.1177/0883073814553272" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25330800">McMillan et al. (2015)</a>, see <a href="#0005">601421.0005</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25330800" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 DEAFNESS, CONGENITAL, AND ADULT-ONSET PROGRESSIVE LEUKOENCEPHALOPATHY</strong>
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KARS1, ARG477HIS (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs778748895;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs778748895</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs778748895 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs778748895;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/rs778748895?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=rs778748895" 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=rs778748895" 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=RCV000986182 OR RCV001293658 OR RCV001293659" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000986182, RCV001293658, RCV001293659" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000986182...</a>
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<p><strong><em>Congenital Deafness and Adult-Onset Progressive Leukoencephalopathy</em></strong></p><p>
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In 2 adult sibs, born of unrelated Chinese Han parents, with congenital deafness and adult-onset progressive leukoencephalopathy (DEAPLE; <a href="/entry/619196">619196</a>), <a href="#22" class="mim-tip-reference" title="Zhou, X.-L., He, L.-X., Yu, L.-J., Wang, Y., Wang, X.-J., Wang, E.-D., Yang, T. <strong>Mutations in KARS cause early-onset hearing loss and leukoencephalopathy: potential pathogenic mechanism.</strong> Hum. Mutat. 38: 1740-1750, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28887846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28887846</a>] [<a href="https://doi.org/10.1002/humu.23335" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28887846">Zhou et al. (2017)</a> identified compound heterozygous missense mutations in the KARS1 gene: a c.1430G-A transition (c.1430G-A, NM_005548.2), resulting in an arg477-to-his (R477H) substitution, and a c.1513C-T transition, resulting in a pro505-to-ser (P505S; <a href="#0008">601421.0008</a>) substitution. These mutations correspond to R505H and P533S, respectively, in the mitochondrial isoform (see <a href="#16" class="mim-tip-reference" title="Scheidecker, S., Bar, S., Stoetzel, C., Geoffroy, V., Lannes, B., Rinaldi, B., Fischer, F., Becker, H. D., Pelletier, V., Pagan, C., Acquaviva-Bourdain, C., Kremer, S., Mirande, M., Tranchant, C., Muller, J., Friant, S., Dollfus, H. <strong>Mutations in KARS cause a severe neurological and neurosensory disease with optic neuropathy.</strong> Hum. Mutat. 40: 1826-1840, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31116475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31116475</a>] [<a href="https://doi.org/10.1002/humu.23799" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31116475">Scheidecker et al., 2019</a>). The mutations, which were found by next-generation sequencing of candidate genes and confirmed by Sanger sequencing, segregated with the disorder in the family. The variants were not present among 1,000 Chinese Han controls. R477H was present at a low frequency (8 x 10(-6)) in the ExAC database, whereas P505S was absent from ExAC. Both mutations affected highly conserved residues in the catalytic domain. In vitro functional expression studies showed that the R477H mutation significantly altered the secondary structure of the protein and impaired the incorporation of KARS into the multiple-synthetase complex (MSC). Expression of both mutations caused abnormal protein aggregation, and both mutations decreased aminoacylation activity (5.7% that of wildtype for the combined mutations). The patients, who were 26 and 21 years of age, had infantile-onset deafness and learning difficulties in childhood, but then presented with progressive cognitive decline later in the second or third decades. Brain imaging showed white matter abnormalities affecting the frontal white matter and corpus callosum. They did not have visual impairment, microcephaly, or seizures; motor abnormalities were not noted. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=28887846+31116475" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Infantile-Onset Progressive Leukoencephalopathy with Deafness</em></strong></p><p>
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In an Italian boy (patient A) with infantile-onset progressive leukoencephalopathy with deafness (LEPID; <a href="/entry/619147">619147</a>) originally reported by <a href="#12" class="mim-tip-reference" title="Orcesi, S., La Piana, R., Uggetti, C., Tonduti, D., Pichiecchio, A., Pasin, M., Viselner, G., Comi, G. P., Del Bo, R., Ronchi, D., Bastianello, S., Balottin, U. <strong>Spinal cord calcification in an early-onset progressive leukoencephalopathy.</strong> J. Child Neurol. 26: 876-880, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21427441/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21427441</a>] [<a href="https://doi.org/10.1177/0883073810390038" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21427441">Orcesi et al. (2011)</a>, <a href="#1" class="mim-tip-reference" title="Ardissone, A., Tonduti, D., Legati, A., Lamantea, E., Barone, R., Dorboz, I., Boespflug-Tanguy, O., Nebbia, G., Maggioni, M., Garavaglia, B., Moroni, I., Farina, L., Pichiecchio, A., Orcesi, S., Chiapparini, L., Ghezzi, D. <strong>KARS-related diseases: progressive leukoencephalopathy with brainstem and spinal cord calcifications as new phenotype and a review of literature.</strong> Orphanet J. Rare Dis. 13: 45, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29615062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29615062</a>] [<a href="https://doi.org/10.1186/s13023-018-0788-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29615062">Ardissone et al. (2018)</a> identified a homozygous c.1514G-A transition (NM_001130089.1) in the KARS1 gene, resulting in an arg505-to-his (R505H) substitution. These authors stated that this was the same mutation identified by <a href="#22" class="mim-tip-reference" title="Zhou, X.-L., He, L.-X., Yu, L.-J., Wang, Y., Wang, X.-J., Wang, E.-D., Yang, T. <strong>Mutations in KARS cause early-onset hearing loss and leukoencephalopathy: potential pathogenic mechanism.</strong> Hum. Mutat. 38: 1740-1750, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28887846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28887846</a>] [<a href="https://doi.org/10.1002/humu.23335" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28887846">Zhou et al. (2017)</a>. The mutation, which was found by whole-exome sequencing, affected a conserved residue. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=28887846+21427441+29615062" 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 Colombian boy with LEPID, <a href="#20" class="mim-tip-reference" title="Vargas, A., Rojas, J., Aivasovsky, I., Vergara, S., Castellanos, M., Prieto, C., Celis, L. <strong>Progressive early-onset leukodystrophy related to biallelic variants in the KARS gene: the first case described in Latin America.</strong> Genes 11: 1437, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33260297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33260297</a>] [<a href="https://doi.org/10.3390/genes11121437" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33260297">Vargas et al. (2020)</a> identified compound heterozygous missense mutations in the KARS1 gene: R477H and A526V (A498V). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Both were present at very low frequencies in public databases. Functional studies of the variants and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33260297" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 DEAFNESS, CONGENITAL, AND ADULT-ONSET PROGRESSIVE LEUKOENCEPHALOPATHY</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">rs1555512658 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555512658;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=rs1555512658" 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=rs1555512658" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the c.1513C-T transition (c.1513C-T, NM_005548.2) in the KARS1 gene, resulting in a pro505-to-ser (P505S) substitution, that was found in compound heterozygous state in 2 adult sibs with congenital deafness and adult-onset progressive leukoencephalopathy (DEAPLE; <a href="/entry/619196">619196</a>) by <a href="#22" class="mim-tip-reference" title="Zhou, X.-L., He, L.-X., Yu, L.-J., Wang, Y., Wang, X.-J., Wang, E.-D., Yang, T. <strong>Mutations in KARS cause early-onset hearing loss and leukoencephalopathy: potential pathogenic mechanism.</strong> Hum. Mutat. 38: 1740-1750, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28887846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28887846</a>] [<a href="https://doi.org/10.1002/humu.23335" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28887846">Zhou et al. (2017)</a>, see <a href="#0007">601421.0007</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28887846" 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> rs201650281 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs201650281;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/rs201650281?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=rs201650281" 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=rs201650281" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><strong><em>Infantile-Onset Progressive Leukoencephalopathy with Deafness</em></strong></p><p>
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In a French girl with infantile-onset progressive leukoencephalopathy with deafness (LEPID; <a href="/entry/619147">619147</a>), <a href="#14" class="mim-tip-reference" title="Ruzzenente, B., Assouline, Z., Barcia, G., Rio, M., Boddaert, N., Munnich, A., Rotig, A., Metodiev, M. D. <strong>Inhibition of mitochondrial translation in fibroblasts from a patient expressing the KARS p.(pro228leu) variant and presenting with sensorineural deafness, developmental delay, and lactic acidosis.</strong> Hum. Mutat. 39: 2047-2059, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30252186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30252186</a>] [<a href="https://doi.org/10.1002/humu.23657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30252186">Ruzzenente et al. (2018)</a> identified compound heterozygous mutations in the KARS1 gene: a c.683C-T transition (c.683C-T, NM_001130089.1), resulting in a pro228-to-leu (P228L) substitution at a highly conserved residue in the anticodon-binding domain, and a 1-bp deletion (c.1438delC; <a href="#0010">601421.0010</a>), resulting in a frameshift and premature termination (Leu480TrpfsTer3). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. P228L has a low frequency (0.014%) in the ExAC database. Analysis of patient cells showed only the P228L mutation, suggesting that the frameshift was subject to nonsense-mediated mRNA decay. Detailed in vitro functional expression studies of patient fibroblasts showed that cytoplasmic translation was intact, but that mitochondrial translation was specifically decreased. There were assembly defects of multiple OXPHOS complexes, which could be rescued by expression of mitochondrial KARS1, but not cytoplasmic KARS1. <a href="#14" class="mim-tip-reference" title="Ruzzenente, B., Assouline, Z., Barcia, G., Rio, M., Boddaert, N., Munnich, A., Rotig, A., Metodiev, M. D. <strong>Inhibition of mitochondrial translation in fibroblasts from a patient expressing the KARS p.(pro228leu) variant and presenting with sensorineural deafness, developmental delay, and lactic acidosis.</strong> Hum. Mutat. 39: 2047-2059, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30252186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30252186</a>] [<a href="https://doi.org/10.1002/humu.23657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30252186">Ruzzenente et al. (2018)</a> concluded that inhibition of mitochondrial translation underlies the disease mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30252186" 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>Congenital Deafness and Adult-Onset Progressive Leukoencephalopathy</em></strong></p><p>
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In a French woman with congenital deafness and adult-onset progressive leukoencephalopathy (DEAPLE; <a href="/entry/619196">619196</a>), <a href="#16" class="mim-tip-reference" title="Scheidecker, S., Bar, S., Stoetzel, C., Geoffroy, V., Lannes, B., Rinaldi, B., Fischer, F., Becker, H. D., Pelletier, V., Pagan, C., Acquaviva-Bourdain, C., Kremer, S., Mirande, M., Tranchant, C., Muller, J., Friant, S., Dollfus, H. <strong>Mutations in KARS cause a severe neurological and neurosensory disease with optic neuropathy.</strong> Hum. Mutat. 40: 1826-1840, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31116475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31116475</a>] [<a href="https://doi.org/10.1002/humu.23799" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31116475">Scheidecker et al. (2019)</a> identified compound heterozygous missense mutations in the KARS1 gene: a c.683C-T transition (c.683C-T, NM_001130089.1), resulting in a pro228-to-leu (P228L) substitution at a moderately conserved residue, and a c.871T-G transversion, resulting in a phe291-to-val (F291V; <a href="#0011">601421.0011</a>) substitution at a conserved residue in the catalytic domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The F291V mutation was not present in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. The P228L and F291V mutations correspond to P200L and F263V in the cytoplasmic isoform. Analysis of patient cells showed increased levels of mitochondrial KARS compared to cytoplasmic KARS, the latter of which showed decreased stability. In vitro immunoprecipitation studies in a yeast 2-hybrid assay showed that the cytoplasmic P200L and F263V mutants had reduced binding to p38 (AIMP2; <a href="/entry/600859">600859</a>). The authors suggested that these mutations may be pathogenic by impairing the association of cytoplasmic KARS with the MSC complex, thus adversely affecting cytoplasmic protein synthesis. These variants also had decreased aminoacylation activity compared to wildtype KARS. Patient skeletal muscle showed decreased activities of mitochondrial complexes I and IV, and there was an overexpression of KARS in the mitochondria, suggesting mitochondrial dysfunction. <a href="#16" class="mim-tip-reference" title="Scheidecker, S., Bar, S., Stoetzel, C., Geoffroy, V., Lannes, B., Rinaldi, B., Fischer, F., Becker, H. D., Pelletier, V., Pagan, C., Acquaviva-Bourdain, C., Kremer, S., Mirande, M., Tranchant, C., Muller, J., Friant, S., Dollfus, H. <strong>Mutations in KARS cause a severe neurological and neurosensory disease with optic neuropathy.</strong> Hum. Mutat. 40: 1826-1840, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31116475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31116475</a>] [<a href="https://doi.org/10.1002/humu.23799" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31116475">Scheidecker et al. (2019)</a> hypothesized that the mitochondrial dysfunction was secondary to defects in cytoplasmic KARS protein synthesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31116475" 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">rs1567498374 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1567498374;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=rs1567498374" 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=rs1567498374" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the c.1438delC mutation (c.1438delC, NM_001130089.1) in the KARS1 gene, resulting in a frameshift and premature termination (Leu480TrpfsTer3), that was found in compound heterozygous state in a patient with infantile-onset progressive leukoencephalopathy with deafness (LEPID; <a href="/entry/619147">619147</a>) by <a href="#14" class="mim-tip-reference" title="Ruzzenente, B., Assouline, Z., Barcia, G., Rio, M., Boddaert, N., Munnich, A., Rotig, A., Metodiev, M. D. <strong>Inhibition of mitochondrial translation in fibroblasts from a patient expressing the KARS p.(pro228leu) variant and presenting with sensorineural deafness, developmental delay, and lactic acidosis.</strong> Hum. Mutat. 39: 2047-2059, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30252186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30252186</a>] [<a href="https://doi.org/10.1002/humu.23657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30252186">Ruzzenente et al. (2018)</a>, see <a href="#0009">601421.0009</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30252186" 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> rs772410450 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs772410450;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/rs772410450?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=rs772410450" 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=rs772410450" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the c.871T-G transversion (c.871T-G, NM_001130089.1) in the KARS1 gene, resulting in a phe291-to-val (F291V) substitution, that was found in compound heterozygous state in a patient with congenital deafness and adult-onset progressive leukoencephalopathy (DEAPLE; <a href="/entry/619196">619196</a>) by <a href="#16" class="mim-tip-reference" title="Scheidecker, S., Bar, S., Stoetzel, C., Geoffroy, V., Lannes, B., Rinaldi, B., Fischer, F., Becker, H. D., Pelletier, V., Pagan, C., Acquaviva-Bourdain, C., Kremer, S., Mirande, M., Tranchant, C., Muller, J., Friant, S., Dollfus, H. <strong>Mutations in KARS cause a severe neurological and neurosensory disease with optic neuropathy.</strong> Hum. Mutat. 40: 1826-1840, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31116475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31116475</a>] [<a href="https://doi.org/10.1002/humu.23799" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31116475">Scheidecker et al. (2019)</a>, see <a href="#0009">601421.0009</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31116475" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 4 patients from 3 unrelated Japanese families (families 1-3) with infantile-onset progressive leukoencephalopathy with deafness (LEPID; <a href="/entry/619147">619147</a>), <a href="#4" class="mim-tip-reference" title="Itoh, M., Dai, H., Horike, S., Gonzalez, J., Kitami, Y., Meguro-Horike, M., Kuki, I., Shimakawa, S., Yoshinaga, H., Ota, Y., Okazaki, T., Maegaki, Y., Nabatame, S., Okazaki, S., Kawawaki, H., Ueno, N., Goto, Y., Kato, Y. <strong>Biallelic KARS pathogenic variants cause an early-onset progressive leukodystrophy.</strong> Brain 142: 560-573, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30715177/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30715177</a>] [<a href="https://doi.org/10.1093/brain/awz001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30715177">Itoh et al. (2019)</a> identified a homozygous c.1786C-T transition (c.1786C-T, NM_001130089.1) in the KARS1 gene, resulting in a leu596-to-phe (L596F) substitution in mitochondrial isoform 1 (leu568-to-phe (L568F) in cytosolic isoform 2). Three additional patients from 2 unrelated Japanese families (families 4 and 5) were compound heterozygous for L596F and another mutation in the KARS1 gene (c.879+1G-A, <a href="#0013">601421.0013</a> and G189D). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families from whom parental DNA was available. The c.879+1G-A mutation resulted in a splicing defect and an in-frame deletion of exon 7 (Glu252_Glu293del). None of the mutations were present in the dbSNP, 1000 Genomes Project, or Japanese control databases. Liver and brain tissue derived from some of the deceased patients showed decreased KARS1 expression levels and decreased aminoacylation activity of both the mitochondrial and cytosolic forms compared to controls. Kars-depleted Xenopus embryos showed developmental defects of the head and eyes, which could be rescued with wildtype KARS, but not by mutant KARS variants found in the patients. Three of the patients, including 2 sibs and an unrelated boy, had previously been reported by <a href="#21" class="mim-tip-reference" title="Yoshimura, M., Hara, T., Maegaki, Y., Koeda, T., Okubo, K., Hamasaki, N., Sly, W. S., Takeshita, K. <strong>A novel neurological disorder with progressive CNS calcification, deafness, renal tubular acidosis, and microcytic anemia.</strong> Dev. Med. Child Neurol. 39: 198-201, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9112970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9112970</a>] [<a href="https://doi.org/10.1111/j.1469-8749.1997.tb07410.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9112970">Yoshimura et al. (1997)</a> and <a href="#6" class="mim-tip-reference" title="Kuki, I., Kawawaki, H., Okazaki, S., Kimura-Ohba, S., Nakano, T., Fukushima, H., Inoue, T., Tomiwa, K., Itoh, M. <strong>Progressive leukoencephalopathy with intracranial calcification, congenital deafness, and developmental deterioration.</strong> Am. J. Med. Genet. 155A: 2832-2837, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21964701/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21964701</a>] [<a href="https://doi.org/10.1002/ajmg.a.34256" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21964701">Kuki et al. (2011)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21964701+9112970+30715177" 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>For discussion of the G-to-A transition (c.879+1G-A, NM_001130089.1) in the KARS1 gene, resulting in a splicing defect and in-frame deletion (Glu252_Glu293del), that was found in compound heterozygous state in 2 sibs with infantile-onset progressive leukoencephalopathy with deafness (LEPID; <a href="/entry/619147">619147</a>) by <a href="#4" class="mim-tip-reference" title="Itoh, M., Dai, H., Horike, S., Gonzalez, J., Kitami, Y., Meguro-Horike, M., Kuki, I., Shimakawa, S., Yoshinaga, H., Ota, Y., Okazaki, T., Maegaki, Y., Nabatame, S., Okazaki, S., Kawawaki, H., Ueno, N., Goto, Y., Kato, Y. <strong>Biallelic KARS pathogenic variants cause an early-onset progressive leukodystrophy.</strong> Brain 142: 560-573, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30715177/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30715177</a>] [<a href="https://doi.org/10.1093/brain/awz001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30715177">Itoh et al. (2019)</a>, see <a href="#0013">601421.0013</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30715177" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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[<a href="https://doi.org/10.1093/brain/awz001" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1177/0883073814553272" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1177/0883073810390038" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0500226102" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.23657" target="_blank">Full Text</a>]
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<strong>Mutations in KARS, encoding lysyl-tRNA synthetase, cause autosomal-recessive nonsyndromic hearing impairment DFNB89.</strong>
|
|
Am. J. Hum. Genet. 93: 132-140, 2013.
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|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23768514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23768514</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23768514[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=23768514" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2013.05.018" 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="16" class="mim-anchor"></a>
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<a id="Scheidecker2019" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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|
Scheidecker, S., Bar, S., Stoetzel, C., Geoffroy, V., Lannes, B., Rinaldi, B., Fischer, F., Becker, H. D., Pelletier, V., Pagan, C., Acquaviva-Bourdain, C., Kremer, S., Mirande, M., Tranchant, C., Muller, J., Friant, S., Dollfus, H.
|
|
<strong>Mutations in KARS cause a severe neurological and neurosensory disease with optic neuropathy.</strong>
|
|
Hum. Mutat. 40: 1826-1840, 2019.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31116475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31116475</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31116475" 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.23799" 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="17" class="mim-anchor"></a>
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<a id="Targoff1993" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Targoff, I. N., Trieu, E. P., Miller, F. W.
|
|
<strong>Reaction of anti-OJ autoantibodies with components of the multi-enzyme complex of aminoacyl-tRNA synthetases in addition to isoleucyl-tRNA synthetase.</strong>
|
|
J. Clin. Invest. 91: 2556-2564, 1993.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8514867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8514867</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8514867" 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/10.1172/JCI116493" 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="18" class="mim-anchor"></a>
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<a id="Tolkunova2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tolkunova, E., Park, H., Xia, J., King, M. P., Davidson, E.
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|
<strong>The human lysyl-tRNA synthetase gene encodes both the cytoplasmic and mitochondrial enzymes by means of an unusual alternative splicing of the primary transcript.</strong>
|
|
J. Biol. Chem. 275: 35063-35069, 2000.
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|
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10952987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10952987</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10952987" 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/10.1074/jbc.M006265200" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="19" class="mim-anchor"></a>
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<a id="van der Knaap2019" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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van der Knaap, M. S., Bugiani, M., Mendes, M. I., Riley, L. G., Smith, D. E. C., Rudinger-Thirion, J., Frugier, M., Breur, M., Crawford, J., van Gaalen, J., Schouten, M., Willems, M., and 10 others.
|
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<strong>Biallelic variants in LARS2 and KARS cause deafness and (ovario)leukodystrophy.</strong>
|
|
Neurology 92: e1225-e1237, 2019. Note: Electronic Article. Erratum: Neurology 93: 982 only, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30737337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30737337</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30737337" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/WNL.0000000000007098" target="_blank">Full Text</a>]
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</li>
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<li>
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<a id="20" class="mim-anchor"></a>
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<a id="Vargas2020" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vargas, A., Rojas, J., Aivasovsky, I., Vergara, S., Castellanos, M., Prieto, C., Celis, L.
|
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<strong>Progressive early-onset leukodystrophy related to biallelic variants in the KARS gene: the first case described in Latin America.</strong>
|
|
Genes 11: 1437, 2020. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33260297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33260297</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33260297" 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/10.3390/genes11121437" target="_blank">Full Text</a>]
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<li>
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<a id="21" class="mim-anchor"></a>
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<a id="Yoshimura1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yoshimura, M., Hara, T., Maegaki, Y., Koeda, T., Okubo, K., Hamasaki, N., Sly, W. S., Takeshita, K.
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<strong>A novel neurological disorder with progressive CNS calcification, deafness, renal tubular acidosis, and microcytic anemia.</strong>
|
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Dev. Med. Child Neurol. 39: 198-201, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9112970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9112970</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9112970" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1469-8749.1997.tb07410.x" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="22" class="mim-anchor"></a>
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<a id="Zhou2017" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhou, X.-L., He, L.-X., Yu, L.-J., Wang, Y., Wang, X.-J., Wang, E.-D., Yang, T.
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<strong>Mutations in KARS cause early-onset hearing loss and leukoencephalopathy: potential pathogenic mechanism.</strong>
|
|
Hum. Mutat. 38: 1740-1750, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28887846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28887846</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28887846" 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.23335" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 02/22/2021
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 02/16/2017<br>Cassandra L. Kniffin - updated : 12/01/2016<br>Ada Hamosh - updated : 8/29/2014<br>Marla J. F. O'Neill - updated : 8/21/2013<br>Cassandra L. Kniffin - updated : 11/15/2010<br>Patricia A. Hartz - updated : 5/16/2007<br>Patricia A. Hartz - updated : 8/6/2002<br>Victor A. McKusick - updated : 6/4/2001
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 9/12/1996
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 03/02/2021
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 03/01/2021<br>ckniffin : 02/22/2021<br>carol : 08/20/2019<br>carol : 01/31/2018<br>carol : 10/20/2017<br>alopez : 02/16/2017<br>carol : 12/02/2016<br>ckniffin : 12/01/2016<br>alopez : 09/17/2015<br>mcolton : 8/18/2015<br>carol : 10/3/2014<br>carol : 9/30/2014<br>alopez : 8/29/2014<br>carol : 9/16/2013<br>carol : 8/27/2013<br>ckniffin : 8/26/2013<br>carol : 8/21/2013<br>carol : 11/17/2010<br>ckniffin : 11/15/2010<br>mgross : 5/22/2007<br>terry : 5/16/2007<br>mgross : 8/6/2002<br>alopez : 6/5/2001<br>terry : 6/4/2001<br>mark : 9/13/1996<br>terry : 9/12/1996<br>mark : 9/12/1996
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
|
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<strong>*</strong> 601421
|
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</span>
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</h3>
|
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</div>
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<div>
|
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<h3>
|
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<span class="mim-font">
|
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|
|
LYSYL-tRNA SYNTHETASE 1; KARS1
|
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
|
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
KARS<br />
|
|
KRS
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: KARS1</em></strong>
|
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</span>
|
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: 16q23.1
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 16:75,627,724-75,647,665 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
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<h4>
|
|
<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="4">
|
|
<span class="mim-font">
|
|
16q23.1
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
?Charcot-Marie-Tooth disease, recessive intermediate, B
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
613641
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
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</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Deafness, autosomal recessive 89
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
613916
|
|
</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">
|
|
Deafness, congenital, and adult-onset progressive leukoencephalopathy
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
619196
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
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<tr>
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Leukoencephalopathy, progressive, infantile-onset, with or without deafness
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<span class="mim-font">
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619147
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<span class="mim-font">
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Autosomal recessive
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<span class="mim-font">
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3
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</tbody>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</h4>
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<p>The KARS gene encodes lysyl-tRNA synthetase, which catalyzes the aminoacylation of tRNA-lys in both the cytoplasm and mitochondria. Protein synthesis is initiated by the attachment of amino acids to cognate tRNAs by aminoacyl-tRNA synthetases (ARSs). At least 6 of 20 human ARSs, including KARS, had been identified as targets of autoantibodies in the autoimmune disease polymyositis/dermatomyositis (Targoff et al. (1993)). </p>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</h4>
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<p>Tolkunova et al. (2000) identified 2 full-length sequences for KARS and determined that they represent cytoplasmic and mitochondrial isoforms. The 625-amino acid mitochondrial enzyme and the 597-amino acid cytoplasmic enzyme are identical over the last 576 amino acids, but the mitochondrial enzyme has a different 49-amino acid N terminus containing a mitochondrial targeting sequence. Transfection of both fluorescence-tagged isoforms into an osteosarcoma cell line showed that the cytoplasmic isoform produced a diffuse, cellwide fluorescence, while the mitochondrial isoform resulted in a punctate pattern that colocalized with mitochondrial markers. Ribonuclease protection analysis indicated that the mRNA encoding the cytoplasmic isoform makes up approximately 70%, and the mitochondrial isoform approximately 30%, of mature KARS transcripts. </p><p>Using massively parallel sequencing and RT-PCR experiments, Santos-Cortez et al. (2013) demonstrated that KARS is expressed in hair cells of zebrafish, chickens, and mice, as well as in maculae of zebrafish and mice. Immunolabeling experiments using mouse vestibular tissue revealed broad distribution of KARS in hair cells and supporting cells, and organ of Corti sections showed KARS localization to inner and outer hair cells, Dieter cells, and basilar membrane. In addition, the tectorial membrane showed a strong affinity for KARS antibody, and KARS labeling was strongest within the spiral ligament, particularly in the area containing type II and type IV fibrocytes. KARS was also strongly localized to the outer and inner sulcus cells and spiral limbus epithelium. </p><p>Lo et al. (2014) reported the discovery of a large number of natural catalytic nulls for each human aminoacyl tRNA synthetase. Splicing events retain noncatalytic domains while ablating the catalytic domain to create catalytic nulls with diverse functions. Each synthetase is converted into several new signaling proteins with biologic activities 'orthogonal' to that of the catalytic parent. The recombinant aminoacyl tRNA synthetase variants had specific biologic activities across a spectrum of cell-based assays: about 46% across all species affect transcriptional regulation, 22% cell differentiation, 10% immunomodulation, 10% cytoprotection, and 4% each for proliferation, adipogenesis/cholesterol transport, and inflammatory response. Lo et al. (2014) identified in-frame splice variants of cytoplasmic aminoacyl tRNA synthetases. They identified 3 catalytic-null splice variants for cytoplasmic LysRS. </p><p>The KARS1 gene encodes both the cytosolic and mitochondrial isoforms of KARS1, which are generated by alternative splicing. The cytoplasmic isoform skips exon 2 and splices exon 1 to exon 3, whereas the mitochondrial isoform includes exon 2. The ATG initiation codons are different between the 2 isoforms. The mitochondrial isoform has 28 more residues than the cytosolic isoform. The cytoplasmic isoform represents about 70% and the mitochondrial isoform about 30% of the mature transcript from the KARS1 gene (summary by Scheidecker et al., 2019). </p>
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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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</h4>
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<span class="mim-text-font">
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<p>Tolkunova et al. (2000) determined that the KARS gene contains 15 exons and spans about 20 kb. The cytoplasmic and mitochondrial KARS isoforms result from alternative splicing of the first 3 exons. Tolkunova et al. (2000) found that the initiation codons for KARS and RAP1 (605061) are separated by 243 bp. This region lacks a conventional TATA sequence but contains several SP1 (189906)-binding domains oriented in both directions. </p>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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<p>Nichols et al. (1996) used Southern hybridization of human/rodent somatic cell hybrids to localize the KARS gene to chromosome 16. By fluorescence in situ hybridization analysis, they assigned the gene to 16q23-q24. By radiation hybrid panel analysis, Maas et al. (2001) mapped KARS and the gene for tRNA-specific adenosine deaminase (ADAT1; 604230) to 16q22.2-q22.3, with alanyl-tRNA synthetase (AARS; 601065) positioned centromeric to these 2 genes. </p>
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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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<p>Tolkunova et al. (2000) found that both full-length mitochondrial and cytoplasmic KARS, purified after expression in E. coli, aminoacylated in vitro transcripts corresponding to both the cytoplasmic and mitochondrial tRNA-lys. </p><p>Park et al. (2005) stated that, in addition to their essential role in protein synthesis, ARSs function as regulators and signaling molecules. KARS can synthesize diadenosine polyphosphates, and this activity plays a role in transcriptional control through MITF (156845). Park et al. (2005) found that KARS was secreted from multiple human cell lines in response to TNF-alpha (TNF; 191160). Secreted KARS bound macrophages and peripheral blood mononuclear cells and enhanced TNF-alpha production and cell migration. The signaling pathways triggered by KARS involved ERK (see MAPK3; 601795), p38 MAPK (MAPK14; 600289), and an inhibitory G protein (see GNAI1, 139310). </p>
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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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<p><strong><em>Charcot-Marie-Tooth Disease, Recessive Intermediate B</em></strong></p><p>
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McLaughlin et al. (2010) noted that mutations in 3 genes encoding aminoacyl-tRNA synthetases, GARS (600287), YARS (603623), and AARS (601065), had been implicated in Charcot-Marie-Tooth (CMT) disease primarily associated with an axonal pathology (CMT2D, 601472; CMTDIC, 608323; and CMT2N, 613287, respectively). They performed a large-scale mutation screen of 37 human ARS genes in a cohort of 355 patients with a phenotype consistent with CMT. One patient was found to be compound heterozygous for 2 mutations in the KARS gene (601421.0001 and 601421.0002). The phenotype was consistent with a recessive intermediate form of CMT (CMTRIB; 613641), but the patient had additional features, including developmental delay, dysmorphic features, and vestibular Schwannoma. Because the patient was adopted, parental studies were not possible. Thus, KARS was the fourth ARS gene associated with CMT disease, indicating that this family of enzymes is specifically critical for axon function. </p><p><strong><em>Autosomal Recessive Deafness 89</em></strong></p><p>
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In affected individuals from 3 consanguineous Pakistani families with nonsyndromic deafness mapping to chromosome 16q21-q23.2, (DFNB89; 613916), Santos-Cortez et al. (2013) identified homozygosity for 2 missense mutations in the KARS gene, Y173H (601421.0003) and D377N (601421.0004), that segregated with disease in the respective families and were not found in ethnically matched controls or in variant databases. Additional testing for evaluation of CMT disease and acoustic neuroma in 3 affected members from 2 of the DFNB89 families showed no evidence of auditory or limb neuropathy. </p><p><strong><em>Infantile-Onset Progressive Leukoencephalopathy with or without Deafness</em></strong></p><p>
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In 2 sibs, born of unrelated parents, with infantile-onset progressive leukoencephalopathy without deafness (LEPID; 619147), McMillan et al. (2015) identified compound heterozygous missense in the KARS1 gene (R438W, 601421.0005 and E525K, 601421.0006). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed, but both mutations occurred in a highly conserved region of the catalytic domain. </p><p>In a male infant (patient 459) with deficiencies of mitochondrial complexes I and IV, Kohda et al. (2016) identified compound heterozygous missense mutations in the KARS1 gene: a c.1343T-A transversion (NM_005548), resulting in a val448-to-asp (V448D) substitution, and a c.953T-C transition, resulting in an ile318-to-thr (I318T) substitution. The mutations, which were found by high-throughput exome sequencing of 142 unrelated patients with childhood-onset mitochondrial respiratory chain complex deficiencies, segregated with the disorder in the family. A cDNA complementation assay revealed that mitochondrial KARS, but not the cytosolic form, successfully rescued the enzyme defects and assembly of complexes I and IV. Clinical details of the patient were limited, but he was noted to have developmental delay, seizures, nystagmus, lactic acidosis, and hypertrophic cardiomyopathy, suggestive of LEPID. </p><p>In 3 unrelated patients with LEPID, Ardissone et al. (2018) identified homozygous or compound heterozygous missense mutations in the KARS1 gene (see, e.g., 601421.0007). The mutations, which were found by whole-exome or next-generation sequencing of a panel, were confirmed by Sanger sequencing and demonstrated to segregate with the disorder in at least 1 family. Functional studies of the variants and studies of patient cells were not performed. </p><p>In a French girl with LEPID, Ruzzenente et al. (2018) identified compound heterozygous mutations in the KARS1 gene (P228L, 601421.0009 and c.1438delC, 601421.0010). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Detailed in vitro functional expression studies of patient fibroblasts showed that cytoplasmic translation was intact, but mitochondrial translation was specifically decreased. There were assembly defects of multiple OXPHOS complexes, which could be rescued by expression of mitochondrial KARS1, but not cytoplasmic KARS1. Ruzzenente et al. (2018) concluded that inhibition of mitochondrial translation underlies the disease mechanism. </p><p>In 7 children from 5 unrelated Japanese families with LEPID, Itoh et al. (2019) identified homozygous or compound heterozygous mutations in the KARS1 gene (see, e.g., 601421.0012 and 601421.0013). The mutations were found by exome sequencing and confirmed by Sanger sequencing; segregation was consistent with autosomal recessive inheritance in the 2 families from whom parental DNA was available. KARS1 expression levels were decreased in patient tissue, including liver and brain, and enzymatic activity of both the mitochondrial and cytosolic isoforms was decreased compared to controls. Kars-depleted Xenopus embryos showed developmental defects of the head and eyes, which could be rescued with wildtype KARS, but not by the mutant KARS variants found in the patients. </p><p><strong><em>Congenital Deafness and Adult-Onset Progressive Leukoencephalopathy</em></strong></p><p>
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In 2 adult sibs, born of unrelated Chinese Han parents, with congenital deafness and adult-onset progressive leukoencephalopathy (DEAPLE; 619196), Zhou et al. (2017) identified compound heterozygous missense mutations in the KARS1 gene (R477H, 601421.0007 and P505S, 601421.0008). These mutations correspond to R505H and P533S, respectively, in the mitochondrial isoform (see Scheidecker et al., 2019). The mutations, which were found by next-generation sequencing of candidate genes and confirmed by Sanger sequencing, segregated with the disorder in the family. Both mutations affected highly conserved residues in the catalytic domain. In vitro functional expression studies showed that the R477H mutation impaired KARS incorporation into the multiple-synthetase complex (MSC). In addition, both mutations caused abnormal protein aggregation and resulted in decreased KARS aminoacylation activity (5.7% that of wildtype for the combined mutations). </p><p>In a 36-year-old man (patient 5) with DEAPLE, van der Knaap et al. (2019) identified compound heterozygous missense mutations in the KARS gene (R108H and V476F). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Patient-derived fibroblasts showed about a 50% decrease in cytosolic KARS aminoacylation activity compared to controls. </p><p>In a French woman with DEAPLE, Scheidecker et al. (2019) identified compound heterozygous missense mutations in the KARS1 gene (P228L, 601421.0009 and F291V, 601421.0011). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The P228L and F291V mutations correspond to P200L and F263V in the cytoplasmic isoform. Analysis of patient cells showed increased levels of mitochondrial KARS compared to cytoplasmic KARS, the latter of which showed decreased stability. In vitro immunoprecipitation studies in a yeast 2-hybrid assay showed that the cytoplasmic P200L and F263V mutants had reduced binding to p38 (AIMP2; 600859). The authors suggested that these mutations may be pathogenic by impairing the association of cytoplasmic KARS with the MSC complex, thus adversely affecting cytoplasmic protein synthesis. These variants also had decreased aminoacylation activity compared to wildtype KARS. Patient skeletal muscle showed decreased activities of mitochondrial complexes I and IV, and there was an overexpression of KARS in the mitochondria, suggesting mitochondrial dysfunction. Scheidecker et al. (2019) hypothesized that the mitochondrial dysfunction was secondary to defects in cytoplasmic KARS protein synthesis. </p>
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<h4>
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<strong>Animal Model</strong>
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<p>In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human KARS is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning). </p>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>13 Selected Examples):</strong>
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</h4>
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<div>
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<p />
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<h4>
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<span class="mim-font">
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<strong>.0001 CHARCOT-MARIE-TOOTH DISEASE, RECESSIVE INTERMEDIATE B (1 patient)</strong>
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</span>
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</h4>
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KARS1, LEU133HIS
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<br />
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SNP: rs267607194,
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gnomAD: rs267607194,
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ClinVar: RCV000008647
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</span>
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</div>
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<span class="mim-text-font">
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<p>In a patient with an intermediate form of autosomal recessive Charcot-Marie-Tooth disease (CMTRIB; 613641), McLaughlin et al. (2010) identified compound heterozygosity for 2 mutations in the KARS gene: a 398T-A transversion resulting in a leu133-to-his (L133H) substitution in a highly conserved residue, and a 2-bp insertion (524insTT; 601421.0002) predicted to result in a frameshift, premature termination, and a null allele, as confirmed in yeast complementation studies. The L133H substitution occurred in an N-terminal anticodon-binding domain adjacent to the dimer-dimer interface. In vitro functional expression assays showed that the L133H mutant had severely impaired enzyme activity, with a 94% loss of catalytic activity compared to wildtype. In addition to peripheral neuropathy, the patient also had developmental delay, self-abusive behavior, dysmorphic features, and vestibular Schwannoma, which McLaughlin et al. (2010) postulated was due to severe loss of KARS function in both the cytoplasm and mitochondria. </p>
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<h4>
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<span class="mim-font">
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<strong>.0002 CHARCOT-MARIE-TOOTH DISEASE, RECESSIVE INTERMEDIATE B (1 patient)</strong>
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</span>
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</h4>
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KARS1, 2-BP INS, 524TT
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<br />
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SNP: rs587776688,
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ClinVar: RCV000008648
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<span class="mim-text-font">
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<p>For discussion of the 2-bp insertion in the KARS gene (524insTT) that was found in compound heterozygous state in a patient with an intermediate form of autosomal recessive Charcot-Marie-Tooth disease (CMTRIB; 613641) by McLaughlin et al. (2010), see 601421.0001. </p>
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<h4>
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<span class="mim-font">
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<strong>.0003 DEAFNESS, AUTOSOMAL RECESSIVE 89</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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KARS1, TYR173HIS
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SNP: rs397514745,
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gnomAD: rs397514745,
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ClinVar: RCV000054525, RCV000627042, RCV001807772
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<span class="mim-text-font">
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<p>In affected individuals from 2 consanguineous Pakistani families with nonsyndromic deafness (DFNB89; 613916), 1 of which (family 4406) had previously been studied by Basit et al. (2011), Santos-Cortez et al. (2013) identified homozygosity for a c.517T-C transition in exon 5 of the KARS gene, resulting in a tyr173-to-his (Y173H) substitution at a highly conserved residue within the beta-2 strand. The mutation segregated with disease in both families and was not found in 325 ethnically matched controls or in variant databases. </p>
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<h4>
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<span class="mim-font">
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<strong>.0004 DEAFNESS, AUTOSOMAL RECESSIVE 89</strong>
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</span>
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</h4>
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KARS1, ASP377ASN
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SNP: rs397514746,
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gnomAD: rs397514746,
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ClinVar: RCV000054526, RCV001775565
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<div>
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<span class="mim-text-font">
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<p>In an affected individual from a consanguineous Pakistani family with nonsyndromic deafness (DFNB89; 613916), previously studied by Basit et al. (2011) (family 4338), Santos-Cortez et al. (2013) identified homozygosity for a c.1129G-A transition in exon 9 of the KARS gene, resulting in an asp377-to-asn (D377N) substitution at a completely conserved residue within alpha-helix 9, predicted to affect the configuration of the tetramer interface. The mutation segregated with disease in the family and was not found in 325 ethnically matched controls or in variant databases. </p>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 LEUKOENCEPHALOPATHY, PROGRESSIVE, INFANTILE-ONSET, WITHOUT DEAFNESS</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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KARS1, ARG438TRP
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SNP: rs761527468,
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gnomAD: rs761527468,
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ClinVar: RCV001293656, RCV004531073
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 sibs, born of unrelated parents, with infantile-onset progressive leukoencephalopathy without deafness (LEPID; 619147), McMillan et al. (2015) identified compound heterozygous missense mutations in the KARS1 gene: a c.1312C-T transition (c.1312C-T, NM_005548.2), resulting in an arg438-to-trp (R438W) substitution, and a c.1573G-A transition, resulting in a glu525-to-lys (E525K; 601421.0006) substitution. Both mutations occurred at a highly conserved region of the catalytic domain. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed. The patients presented in infancy with visual impairment, progressive microcephaly, and global developmental delay with poor language acquisition. They also had seizures that could be controlled with medication. Neither was deaf. Brain imaging showed subcortical white matter abnormalities with delayed myelination and thin corpus callosum. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 LEUKOENCEPHALOPATHY, PROGRESSIVE, INFANTILE-ONSET, WITHOUT DEAFNESS</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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KARS1, GLU525LYS
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<br />
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SNP: rs770522582,
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gnomAD: rs770522582,
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ClinVar: RCV001293657
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the c.1573G-A transition (c.1573G-A, NM_005548.2) in the KARS1 gene, resulting in a glu525-to-lys (E525K) substitution, that was found in compound heterozygous state in 2 sibs with infantile-onset progressive leukoencephalopathy without deafness (LEPID; 619147) by McMillan et al. (2015), see 601421.0005. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 DEAFNESS, CONGENITAL, AND ADULT-ONSET PROGRESSIVE LEUKOENCEPHALOPATHY</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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LEUKOENCEPHALOPATHY, PROGRESSIVE, INFANTILE-ONSET, WITH DEAFNESS, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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KARS1, ARG477HIS ({dbSNP rs778748895})
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<br />
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SNP: rs778748895,
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gnomAD: rs778748895,
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ClinVar: RCV000986182, RCV001293658, RCV001293659
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p />
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<p><strong><em>Congenital Deafness and Adult-Onset Progressive Leukoencephalopathy</em></strong></p><p>
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In 2 adult sibs, born of unrelated Chinese Han parents, with congenital deafness and adult-onset progressive leukoencephalopathy (DEAPLE; 619196), Zhou et al. (2017) identified compound heterozygous missense mutations in the KARS1 gene: a c.1430G-A transition (c.1430G-A, NM_005548.2), resulting in an arg477-to-his (R477H) substitution, and a c.1513C-T transition, resulting in a pro505-to-ser (P505S; 601421.0008) substitution. These mutations correspond to R505H and P533S, respectively, in the mitochondrial isoform (see Scheidecker et al., 2019). The mutations, which were found by next-generation sequencing of candidate genes and confirmed by Sanger sequencing, segregated with the disorder in the family. The variants were not present among 1,000 Chinese Han controls. R477H was present at a low frequency (8 x 10(-6)) in the ExAC database, whereas P505S was absent from ExAC. Both mutations affected highly conserved residues in the catalytic domain. In vitro functional expression studies showed that the R477H mutation significantly altered the secondary structure of the protein and impaired the incorporation of KARS into the multiple-synthetase complex (MSC). Expression of both mutations caused abnormal protein aggregation, and both mutations decreased aminoacylation activity (5.7% that of wildtype for the combined mutations). The patients, who were 26 and 21 years of age, had infantile-onset deafness and learning difficulties in childhood, but then presented with progressive cognitive decline later in the second or third decades. Brain imaging showed white matter abnormalities affecting the frontal white matter and corpus callosum. They did not have visual impairment, microcephaly, or seizures; motor abnormalities were not noted. </p><p><strong><em>Infantile-Onset Progressive Leukoencephalopathy with Deafness</em></strong></p><p>
|
|
In an Italian boy (patient A) with infantile-onset progressive leukoencephalopathy with deafness (LEPID; 619147) originally reported by Orcesi et al. (2011), Ardissone et al. (2018) identified a homozygous c.1514G-A transition (NM_001130089.1) in the KARS1 gene, resulting in an arg505-to-his (R505H) substitution. These authors stated that this was the same mutation identified by Zhou et al. (2017). The mutation, which was found by whole-exome sequencing, affected a conserved residue. Functional studies of the variant and studies of patient cells were not performed. </p><p>In a Colombian boy with LEPID, Vargas et al. (2020) identified compound heterozygous missense mutations in the KARS1 gene: R477H and A526V (A498V). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Both were present at very low frequencies in public databases. Functional studies of the variants and studies of patient cells were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0008 DEAFNESS, CONGENITAL, AND ADULT-ONSET PROGRESSIVE LEUKOENCEPHALOPATHY</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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KARS1, PRO505SER
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<br />
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SNP: rs1555512658,
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ClinVar: RCV000504639, RCV001293660
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>For discussion of the c.1513C-T transition (c.1513C-T, NM_005548.2) in the KARS1 gene, resulting in a pro505-to-ser (P505S) substitution, that was found in compound heterozygous state in 2 adult sibs with congenital deafness and adult-onset progressive leukoencephalopathy (DEAPLE; 619196) by Zhou et al. (2017), see 601421.0007. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0009 LEUKOENCEPHALOPATHY, PROGRESSIVE, INFANTILE-ONSET, WITH DEAFNESS</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">
|
|
DEAFNESS, CONGENITAL, AND ADULT-ONSET PROGRESSIVE LEUKOENCEPHALOPATHY, INCLUDED
|
|
</span>
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</div>
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<div>
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<span class="mim-text-font">
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KARS1, PRO228LEU ({dbSNP rs201650281})
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<br />
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SNP: rs201650281,
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gnomAD: rs201650281,
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|
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ClinVar: RCV000210691, RCV000681462, RCV000986183, RCV001265601, RCV001293661, RCV001293662, RCV001526444, RCV001775672, RCV002463662, RCV003147413, RCV004699121
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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 />
|
|
<p><strong><em>Infantile-Onset Progressive Leukoencephalopathy with Deafness</em></strong></p><p>
|
|
In a French girl with infantile-onset progressive leukoencephalopathy with deafness (LEPID; 619147), Ruzzenente et al. (2018) identified compound heterozygous mutations in the KARS1 gene: a c.683C-T transition (c.683C-T, NM_001130089.1), resulting in a pro228-to-leu (P228L) substitution at a highly conserved residue in the anticodon-binding domain, and a 1-bp deletion (c.1438delC; 601421.0010), resulting in a frameshift and premature termination (Leu480TrpfsTer3). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. P228L has a low frequency (0.014%) in the ExAC database. Analysis of patient cells showed only the P228L mutation, suggesting that the frameshift was subject to nonsense-mediated mRNA decay. Detailed in vitro functional expression studies of patient fibroblasts showed that cytoplasmic translation was intact, but that mitochondrial translation was specifically decreased. There were assembly defects of multiple OXPHOS complexes, which could be rescued by expression of mitochondrial KARS1, but not cytoplasmic KARS1. Ruzzenente et al. (2018) concluded that inhibition of mitochondrial translation underlies the disease mechanism. </p><p><strong><em>Congenital Deafness and Adult-Onset Progressive Leukoencephalopathy</em></strong></p><p>
|
|
In a French woman with congenital deafness and adult-onset progressive leukoencephalopathy (DEAPLE; 619196), Scheidecker et al. (2019) identified compound heterozygous missense mutations in the KARS1 gene: a c.683C-T transition (c.683C-T, NM_001130089.1), resulting in a pro228-to-leu (P228L) substitution at a moderately conserved residue, and a c.871T-G transversion, resulting in a phe291-to-val (F291V; 601421.0011) substitution at a conserved residue in the catalytic domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The F291V mutation was not present in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. The P228L and F291V mutations correspond to P200L and F263V in the cytoplasmic isoform. Analysis of patient cells showed increased levels of mitochondrial KARS compared to cytoplasmic KARS, the latter of which showed decreased stability. In vitro immunoprecipitation studies in a yeast 2-hybrid assay showed that the cytoplasmic P200L and F263V mutants had reduced binding to p38 (AIMP2; 600859). The authors suggested that these mutations may be pathogenic by impairing the association of cytoplasmic KARS with the MSC complex, thus adversely affecting cytoplasmic protein synthesis. These variants also had decreased aminoacylation activity compared to wildtype KARS. Patient skeletal muscle showed decreased activities of mitochondrial complexes I and IV, and there was an overexpression of KARS in the mitochondria, suggesting mitochondrial dysfunction. Scheidecker et al. (2019) hypothesized that the mitochondrial dysfunction was secondary to defects in cytoplasmic KARS protein synthesis. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
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<br />
|
|
</div>
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|
|
|
</div>
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|
|
|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 LEUKOENCEPHALOPATHY, PROGRESSIVE, INFANTILE-ONSET, WITH DEAFNESS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
KARS1, 1-BP DEL, 1438C
|
|
|
|
|
|
<br />
|
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|
|
SNP: rs1567498374,
|
|
|
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|
|
|
ClinVar: RCV000678489, RCV001293663, RCV005091975
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.1438delC mutation (c.1438delC, NM_001130089.1) in the KARS1 gene, resulting in a frameshift and premature termination (Leu480TrpfsTer3), that was found in compound heterozygous state in a patient with infantile-onset progressive leukoencephalopathy with deafness (LEPID; 619147) by Ruzzenente et al. (2018), see 601421.0009. </p>
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<br />
|
|
</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>.0011 DEAFNESS, CONGENITAL, AND ADULT-ONSET PROGRESSIVE LEUKOENCEPHALOPATHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
KARS1, PHE291VAL
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|
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<br />
|
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|
|
SNP: rs772410450,
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|
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|
|
|
gnomAD: rs772410450,
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|
|
|
|
|
ClinVar: RCV000681463, RCV001200599, RCV001293664, RCV001374667
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.871T-G transversion (c.871T-G, NM_001130089.1) in the KARS1 gene, resulting in a phe291-to-val (F291V) substitution, that was found in compound heterozygous state in a patient with congenital deafness and adult-onset progressive leukoencephalopathy (DEAPLE; 619196) by Scheidecker et al. (2019), see 601421.0009. </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>.0012 LEUKOENCEPHALOPATHY, PROGRESSIVE, INFANTILE-ONSET, WITH DEAFNESS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
KARS1, LEU596PHE
|
|
|
|
|
|
<br />
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|
|
|
SNP: rs768349236,
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|
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|
|
|
gnomAD: rs768349236,
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|
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|
|
ClinVar: RCV001293665
|
|
|
|
|
|
</span>
|
|
</div>
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 patients from 3 unrelated Japanese families (families 1-3) with infantile-onset progressive leukoencephalopathy with deafness (LEPID; 619147), Itoh et al. (2019) identified a homozygous c.1786C-T transition (c.1786C-T, NM_001130089.1) in the KARS1 gene, resulting in a leu596-to-phe (L596F) substitution in mitochondrial isoform 1 (leu568-to-phe (L568F) in cytosolic isoform 2). Three additional patients from 2 unrelated Japanese families (families 4 and 5) were compound heterozygous for L596F and another mutation in the KARS1 gene (c.879+1G-A, 601421.0013 and G189D). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families from whom parental DNA was available. The c.879+1G-A mutation resulted in a splicing defect and an in-frame deletion of exon 7 (Glu252_Glu293del). None of the mutations were present in the dbSNP, 1000 Genomes Project, or Japanese control databases. Liver and brain tissue derived from some of the deceased patients showed decreased KARS1 expression levels and decreased aminoacylation activity of both the mitochondrial and cytosolic forms compared to controls. Kars-depleted Xenopus embryos showed developmental defects of the head and eyes, which could be rescued with wildtype KARS, but not by mutant KARS variants found in the patients. Three of the patients, including 2 sibs and an unrelated boy, had previously been reported by Yoshimura et al. (1997) and Kuki et al. (2011). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0013 LEUKOENCEPHALOPATHY, PROGRESSIVE, INFANTILE-ONSET, WITH DEAFNESS</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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KARS1, IVS7DS, G-A, +1
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<br />
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SNP: rs2082153181,
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|
|
ClinVar: RCV001293666
|
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</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
|
|
<p>For discussion of the G-to-A transition (c.879+1G-A, NM_001130089.1) in the KARS1 gene, resulting in a splicing defect and in-frame deletion (Glu252_Glu293del), that was found in compound heterozygous state in 2 sibs with infantile-onset progressive leukoencephalopathy with deafness (LEPID; 619147) by Itoh et al. (2019), see 601421.0013. </p>
|
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</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
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</span>
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</h4>
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<div>
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<p />
|
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
|
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Ardissone, A., Tonduti, D., Legati, A., Lamantea, E., Barone, R., Dorboz, I., Boespflug-Tanguy, O., Nebbia, G., Maggioni, M., Garavaglia, B., Moroni, I., Farina, L., Pichiecchio, A., Orcesi, S., Chiapparini, L., Ghezzi, D.
|
|
<strong>KARS-related diseases: progressive leukoencephalopathy with brainstem and spinal cord calcifications as new phenotype and a review of literature.</strong>
|
|
Orphanet J. Rare Dis. 13: 45, 2018. Note: Electronic Article.
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|
[PubMed: 29615062]
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[Full Text: https://doi.org/10.1186/s13023-018-0788-4]
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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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Basit, S., Lee, K., Habib, R., Chen, L., Kalsoom, U., Santos-Cortez, R. L. P., Azeem, Z., Andrade, P., Ansar, M., Ahmad, W., Leal, S. M.
|
|
<strong>DFNB89, a novel autosomal recessive nonsyndromic hearing impairment locus on chromosome 16q21-q23.2.</strong>
|
|
Hum. Genet. 129: 379-285, 2011.
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[PubMed: 21181198]
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[Full Text: https://doi.org/10.1007/s00439-010-0934-0]
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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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Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others.
|
|
<strong>High-throughput discovery of novel developmental phenotypes.</strong>
|
|
Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017.
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[PubMed: 27626380]
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[Full Text: https://doi.org/10.1038/nature19356]
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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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<p>
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Thank you in advance for your generous support, <br />
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Ada Hamosh, MD, MPH <br />
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Scientific Director, OMIM <br />
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