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Entry
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- *600574 - LEUCINE ZIPPER-LIKE TRANSCRIPTIONAL REGULATOR 1; LZTR1
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*600574</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<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 role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<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/600574">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<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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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000099949;t=ENST00000646124" 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=8216" 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=600574" 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=ENSG00000099949;t=ENST00000646124" 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_006767" 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_006767" 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=600574" 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=08992&isoform_id=08992_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/LZTR1" 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/809501,29839558,47717139,49114072,90403050,119623328,189069250,221041296,308219230" 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/Q8N653" 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=8216" 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=ENSG00000099949;t=ENST00000646124" 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=LZTR1" 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=LZTR1" 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+8216" 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/LZTR1" 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:8216" 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/8216" 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=chr22&hgg_gene=ENST00000646124.2&hgg_start=20982297&hgg_end=20999032&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:6742" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/lztr1" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=600574[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=600574[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/LZTR1/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/ENSG00000099949" 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=LZTR1" 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=LZTR1" 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=LZTR1" 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=LZTR1&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/PA30506" 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:6742" 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/FBgn0040344.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:1914113" 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/LZTR1#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:1914113" 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/8216/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=8216" 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://zfin.org/ZDB-GENE-030131-9564" 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://reactome.org/content/query?q=LZTR1&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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600574
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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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LEUCINE ZIPPER-LIKE TRANSCRIPTIONAL REGULATOR 1; LZTR1
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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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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=LZTR1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">LZTR1</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>
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Cytogenetic location: <a href="/geneMap/22/71?start=-3&limit=10&highlight=71">22q11.21</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr22:20982297-20999032&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'})">22:20,982,297-20,999,032</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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<span class="hidden-sm hidden-xs pull-right">
|
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<a href="/clinicalSynopsis/table?mimNumber=615670,616564,605275" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="3">
|
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<span class="mim-font">
|
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<a href="/geneMap/22/71?start=-3&limit=10&highlight=71">
|
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22q11.21
|
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</a>
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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{Schwannomatosis-2, susceptibility to}
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/615670"> 615670 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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<tr>
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<td>
|
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<span class="mim-font">
|
|
Noonan syndrome 10
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
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<a href="/entry/616564"> 616564 </a>
|
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|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
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|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
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<span class="mim-font">
|
|
Noonan syndrome 2
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<a href="/entry/605275"> 605275 </a>
|
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|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/600574" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/600574" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
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<p>The LZTR1 gene encodes a protein that belongs to a functionally diverse superfamily of BTB/POZ (broad complex, tramtrack, and bric-a-brac/poxvirus and zinc finger) proteins. BTB-containing proteins control fundamental cellular processes, ranging from the regulation of chromatin conformation to the cell cycle (summary by <a href="#8" class="mim-tip-reference" title="Piotrowski, A., Xie, J., Liu, Y. F., Poplawski, A. B., Gomes, A. R., Madanecki, P., Fu, C., Crowley, M. R., Crossman, D. K., Armstrong, L., Babovic-Vuksanovic, D., Bergner, A., and 16 others. <strong>Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas.</strong> Nature Genet. 46: 182-187, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24362817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24362817</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24362817[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24362817">Piotrowski et al., 2014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24362817" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By a microdissection and microcloning method, <a href="#6" class="mim-tip-reference" title="Kurahashi, H., Akagi, K., Inazawa, J., Ohta, T., Niikawa, N., Kayatani, F., Sano, T., Okada, S., Nishisho, I. <strong>Isolation and characterization of a novel gene deleted in DiGeorge syndrome.</strong> Hum. Molec. Genet. 4: 541-549, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7633402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7633402</a>] [<a href="https://doi.org/10.1093/hmg/4.4.541" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7633402">Kurahashi et al. (1995)</a> constructed a specific plasmid library from the 22q11 region which is commonly deleted in the DiGeorge syndrome (DGS; <a href="/entry/188400">188400</a>). Dosage analysis proved that 3 of 144 randomly selected microclones detected hemizygosity in 2 patients with DGS. They then obtained 2 cosmid contigs corresponding to the microclones and using 1 of the cosmids of 1 of the contigs identified a 4.3-kb cDNA from a fetal brain cDNA library. Sequence analysis of the cDNA revealed an open reading frame encoding 552 amino acids that had several characteristics of DNA-binding proteins. The gene, designated LZTR1 (for leucine-zipper-like transcriptional regulator-1) by them, was transcribed in several essential fetal organs and proved to be hemizygously deleted in 7 of 8 DGS patients or its variants. Although LZTR1 did not locate in the shortest region of overlap of DGS, several of its structural characteristics identified it as a transcriptional regulator, suggesting that it plays a crucial role in embryogenesis and that haploinsufficiency of this gene may be partly responsible for the developmental abnormalities of DGS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7633402" 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>Using immunoprecipitation of endogenous LZTR1 followed by Western blotting, <a href="#10" class="mim-tip-reference" title="Umeki, I., Niihori, T., Abe, T., Kanno, S., Okamoto, N., Mizuno, S., Kurosawa, K., Nagasaki, K., Yoshida, M., Ohashi, H., Inoue, S., Matsubara, Y., Fujiwara, I., Kure, S., Aoki, Y. <strong>Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes.</strong> Hum. Genet. 138: 21-35, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30368668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30368668</a>] [<a href="https://doi.org/10.1007/s00439-018-1951-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30368668">Umeki et al. (2019)</a> showed that LZTR1 bound to the RAF1 (<a href="/entry/164760">164760</a>)-SHOC2 (<a href="/entry/602775">602775</a>)-PPP1CB (<a href="/entry/600590">600590</a>) complex. Mutations in these genes cause Noonan syndrome or Noonan-like phenotypes. Cells transfected with siRNA against LZTR1 exhibited decreased levels of RAF1 phosphorylated at ser259. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30368668" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By trapping LZTR1 complexes from intact mammalian cells, <a href="#9" class="mim-tip-reference" title="Steklov, M., Pandolfi, S., Baietti, M. F., Batiuk, A., Carai, P., Najm, P., Zhang, M., Jang, H., Renzi, F., Cai, Y., Asbagh, L. A., Pastor, T., and 13 others. <strong>Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination.</strong> Science 362: 1177-1182, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30442762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30442762</a>] [<a href="https://doi.org/10.1126/science.aap7607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30442762">Steklov et al. (2018)</a> identified the guanosine triphosphatase RAS (see <a href="/entry/190020">190020</a>) as a substrate for the LZTR1-CUL3 complex. Ubiquitome analysis showed that loss of Lztr1 abrogated Ras ubiquitination at lysine-170. LZTR1-mediated ubiquitination inhibited RAS signaling by attenuating its association with the membrane. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30442762" 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="#1" class="mim-tip-reference" title="Bigenzahn, J. W., Collu, G. M., Kartnig, F., Pieraks, M., Vladimer, G. I., Heinz, L. X., Sedlyarov, V., Schischlik, F., Fauster, A., Rebsamen, M., Parapatics, K., Blomen, V. A., Muller, A. C., Winter, G. E., Kralovics, R., Brummelkamp, T. R., Mlodzik, M., Superti-Furga, G. <strong>LZTR1 is a regulator of RAS ubiquitination and signaling.</strong> Science 362: 1171-1177, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30442766/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30442766</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30442766[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.aap8210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30442766">Bigenzahn et al. (2018)</a> found that knockdown of the Drosophila LZTR1 ortholog CG3711 resulted in a Ras-dependent gain-of-function phenotype. Endogenous human LZTR1 associates with the main RAS isoforms. Inactivation of LZTR1 led to decreased ubiquitination and enhanced plasma membrane localization of endogenous KRAS (<a href="/entry/190070">190070</a>). <a href="#1" class="mim-tip-reference" title="Bigenzahn, J. W., Collu, G. M., Kartnig, F., Pieraks, M., Vladimer, G. I., Heinz, L. X., Sedlyarov, V., Schischlik, F., Fauster, A., Rebsamen, M., Parapatics, K., Blomen, V. A., Muller, A. C., Winter, G. E., Kralovics, R., Brummelkamp, T. R., Mlodzik, M., Superti-Furga, G. <strong>LZTR1 is a regulator of RAS ubiquitination and signaling.</strong> Science 362: 1171-1177, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30442766/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30442766</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30442766[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.aap8210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30442766">Bigenzahn et al. (2018)</a> proposed that LZTR1 acts as a conserved regulator of RAS ubiquitination and MAPK pathway activation. 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<p>The LZTR1 gene maps to chromosome 22q11 (<a href="#6" class="mim-tip-reference" title="Kurahashi, H., Akagi, K., Inazawa, J., Ohta, T., Niikawa, N., Kayatani, F., Sano, T., Okada, S., Nishisho, I. <strong>Isolation and characterization of a novel gene deleted in DiGeorge syndrome.</strong> Hum. Molec. Genet. 4: 541-549, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7633402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7633402</a>] [<a href="https://doi.org/10.1093/hmg/4.4.541" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7633402">Kurahashi et al., 1995</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7633402" 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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In 16 of 20 probands with schwannomatosis-2 (SWN2; <a href="/entry/615670">615670</a>), <a href="#8" class="mim-tip-reference" title="Piotrowski, A., Xie, J., Liu, Y. F., Poplawski, A. B., Gomes, A. R., Madanecki, P., Fu, C., Crowley, M. R., Crossman, D. K., Armstrong, L., Babovic-Vuksanovic, D., Bergner, A., and 16 others. <strong>Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas.</strong> Nature Genet. 46: 182-187, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24362817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24362817</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24362817[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24362817">Piotrowski et al. (2014)</a> identified 15 different germline heterozygous mutations in the LZTR1 gene (see, e.g., <a href="#0001">600574.0001</a>-<a href="#0006">600574.0006</a>). There were 6 truncating mutations, 1 in-frame splice site mutation, 1 deletion affecting a splice site, and 7 missense mutations at highly conserved residues. All schwannomas studied also carried the heterozygous LZTR1 mutation, and all showed loss of heterozygosity (LOH) at chromosome 22q11, including the LZTR1, SMARCB1 (<a href="/entry/601607">601607</a>), and NF2 (<a href="/entry/607379">607379</a>) genes. In addition, all tumors from all patients carried a heterozygous somatic mutation in the NF2 gene. These findings were consistent with biallelic loss of function of both LZTR1 and NF2 in all tumors. Functional studies of the variants were not performed. <a href="#8" class="mim-tip-reference" title="Piotrowski, A., Xie, J., Liu, Y. F., Poplawski, A. B., Gomes, A. R., Madanecki, P., Fu, C., Crowley, M. R., Crossman, D. K., Armstrong, L., Babovic-Vuksanovic, D., Bergner, A., and 16 others. <strong>Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas.</strong> Nature Genet. 46: 182-187, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24362817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24362817</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24362817[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24362817">Piotrowski et al. (2014)</a> characterized the pathogenesis of tumor development as resulting from 3 mutational events: a germline LZTR1 mutation (E1), a deletion of 22q that includes the LZTR1 and NF2 genes (E2), and a somatic NF2 mutation (E3). None of the patients or tumors carried a SMARCB1 mutation. The germline mutations segregated with the disorder in all available affected first-degree relatives, although 4 asymptomatic parents also carried the mutation, indicating incomplete penetrance. The findings suggested that loss of LZTR1 function can predispose to the development of autosomal dominant multiple schwannomas, thus implicating LZTR1 as a tumor suppressor gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24362817" 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>Noonan Syndrome 10</em></strong></p><p>
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In affected members of 5 families with Noonan syndrome-10 (NS10; <a href="/entry/616564">616564</a>), <a href="#11" class="mim-tip-reference" title="Yamamoto, G. L., Aguena, M., Gos, M., Hung, C., Pilch, J., Fahiminiya, S., Abramowicz, A., Cristian, I., Buscarilli, M., Naslavsky, M. S., Malaquias, A. C., Zatz, M., Bodamer, O., Majewski, J., Jorge, A. A. L., Pereira, A. C., Kim, C. A., Passos-Bueno, M. R., Bertola, D. R. <strong>Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome.</strong> J. Med. Genet. 52: 413-421, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25795793/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25795793</a>] [<a href="https://doi.org/10.1136/jmedgenet-2015-103018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25795793">Yamamoto et al. (2015)</a> identified 5 different heterozygous missense mutations in the LZTR1 gene (see, e.g., <a href="#0007">600574.0007</a>-<a href="#0009">600574.0009</a>). All of the mutations occurred in the Kelch (KT) domains, but functional studies of the variants were not performed. Mutations in 4 of the families were found by whole-exome sequencing of a cohort of 50 Brazilian patients with Noonan syndrome; the fifth family was of Polish origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25795793" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Umeki, I., Niihori, T., Abe, T., Kanno, S., Okamoto, N., Mizuno, S., Kurosawa, K., Nagasaki, K., Yoshida, M., Ohashi, H., Inoue, S., Matsubara, Y., Fujiwara, I., Kure, S., Aoki, Y. <strong>Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes.</strong> Hum. Genet. 138: 21-35, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30368668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30368668</a>] [<a href="https://doi.org/10.1007/s00439-018-1951-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30368668">Umeki et al. (2019)</a> reported 6 NS10 patients with heterozygous mutations in LZTR1. All patients had cardiac defects; other features were more variable. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30368668" 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>Noonan Syndrome 2</em></strong></p><p>
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<a href="#5" class="mim-tip-reference" title="Johnston, J. J., van der Smagt, J. J., Rosenfeld, J. A., Pagnamenta, A. T., Alswaid, A., Baker, E. H., Blair, E., Borck, G., Brinkmann, J., Craigen, W., Dung, V. C., Emrick, L., and 25 others. <strong>Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.</strong> Genet. Med. 20: 1175-1185, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29469822/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29469822</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29469822[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/gim.2017.249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29469822">Johnston et al. (2018)</a> reported 17 mutations in 12 families with autosomal recessive Noonan syndrome (NS2; <a href="/entry/605275">605275</a>). These included missense, nonsense, frameshift, and splice site mutations that occurred in homozygosity or compound heterozygosity. All parents were heterozygous and unaffected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29469822" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Umeki, I., Niihori, T., Abe, T., Kanno, S., Okamoto, N., Mizuno, S., Kurosawa, K., Nagasaki, K., Yoshida, M., Ohashi, H., Inoue, S., Matsubara, Y., Fujiwara, I., Kure, S., Aoki, Y. <strong>Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes.</strong> Hum. Genet. 138: 21-35, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30368668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30368668</a>] [<a href="https://doi.org/10.1007/s00439-018-1951-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30368668">Umeki et al. (2019)</a> reported 1 NS2 patient with compound heterozygous mutations in the LZTR1 gene as well as 6 NS10 patients with heterozygous mutations in LZTR1. All patients had cardiac defects and 71%, including the NS2 patient, had hypertrophic cardiomyopathy. Other features were more variable. The patient with NS2 inherited each mutation from one of her unaffected parents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30368668" 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>Functional Studies of LZTR1 Mutations</em></strong></p><p>
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Using transfected COS-1 and HEK293T cells, <a href="#7" class="mim-tip-reference" title="Motta, M., Fidan, M., Bellacchio, E., Pantaleoni, F., Schneider-Heieck, K., Coppola, S., Borck, G., Salviati, L., Zenker, M., Cirstea, I. C., Tartaglia, M. <strong>Dominant Noonan syndrome-causing LZTR1 mutations specifically affect the Kelch domain substrate-recognition surface and enhance RAS-MAPK signaling.</strong> Hum. Molec. Genet. 28: 1007-1022, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30481304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30481304</a>] [<a href="https://doi.org/10.1093/hmg/ddy412" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30481304">Motta et al. (2019)</a> found that the NS-causing dominant mutations in LZTR1 did not impact protein stability or Golgi localization, but they enhanced stimulus-dependent RAS-MAPK signaling. In contrast, NS-causing recessive mutations in LZTR1 caused loss of function by affecting either protein stability or Golgi localization, but they had no impact on RAS-MAPK signaling. Coimmunoprecipitation analysis showed that NS-causing dominant mutations in LZTR1 did not affect BTB domain-mediated binding to CUL3 (<a href="/entry/603136">603136</a>). Structural analysis suggested that NS-causing dominant mutations in LZTR1 affected the substrate-binding Kelch domain of LZTR1, which mediates binding of substrate to the CUL3-RING ubiquitin ligase complex to promote substrate ubiquitination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30481304" 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="#9" class="mim-tip-reference" title="Steklov, M., Pandolfi, S., Baietti, M. F., Batiuk, A., Carai, P., Najm, P., Zhang, M., Jang, H., Renzi, F., Cai, Y., Asbagh, L. A., Pastor, T., and 13 others. <strong>Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination.</strong> Science 362: 1177-1182, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30442762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30442762</a>] [<a href="https://doi.org/10.1126/science.aap7607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30442762">Steklov et al. (2018)</a> found that LZTR1 haploinsufficiency in mice recapitulated Noonan syndrome phenotypes, whereas LZTR1 loss in Schwann cells drove differentiation and proliferation. Loss of Lztr1 was lethal between embryonic day embryonic day 17.5 and birth. Lztr1 +/- male mice exhibited decreased weight and facial dysmorphia. Lztr1 +/- mice, both male and female, displayed heart malformations, including decreased left ventricular systolic function, increased diastolic dimensions, eccentric hypertrophy, increased cardiomyocyte area, and reduced longevity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30442762" 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="#2" class="mim-tip-reference" title="Castel, P., Cheng, A., Cuevas-Navarro, A., Everman, D. B., Papageorge, A. G., Simanshu, D. K., Tankka, A., Galeas, J., Urisman, A., McCormick, F. <strong>RIT1 oncoproteins escape LZTR1-mediated proteolysis.</strong> Science 363: 1226-1230, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30872527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30872527</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30872527[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.aav1444" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30872527">Castel et al. (2019)</a> used an isogenic germline knockin mouse model to study the effects of RIT1 (<a href="/entry/609591">609591</a>) mutation at the organismal level, which resulted in a phenotype resembling Noonan syndrome. By mass spectrometry, <a href="#2" class="mim-tip-reference" title="Castel, P., Cheng, A., Cuevas-Navarro, A., Everman, D. B., Papageorge, A. G., Simanshu, D. K., Tankka, A., Galeas, J., Urisman, A., McCormick, F. <strong>RIT1 oncoproteins escape LZTR1-mediated proteolysis.</strong> Science 363: 1226-1230, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30872527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30872527</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30872527[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.aav1444" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30872527">Castel et al. (2019)</a> detected a RIT1 interactor, LZTR1, that acts as an adaptor for protein degradation. Pathogenic mutations affecting either RIT1 or LZTR1 resulted in incomplete degradation of RIT1. This led to RIT1 accumulation and dysregulated growth factor signaling responses. <a href="#2" class="mim-tip-reference" title="Castel, P., Cheng, A., Cuevas-Navarro, A., Everman, D. B., Papageorge, A. G., Simanshu, D. K., Tankka, A., Galeas, J., Urisman, A., McCormick, F. <strong>RIT1 oncoproteins escape LZTR1-mediated proteolysis.</strong> Science 363: 1226-1230, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30872527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30872527</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30872527[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.aav1444" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30872527">Castel et al. (2019)</a> concluded that their results highlighted a mechanism of pathogenesis that relies on impaired protein degradation of the Ras GTPase RIT1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30872527" 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> rs587777176 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777176;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/rs587777176?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=rs587777176" 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=rs587777176" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a father and 2 of his adult children with schwannomatosis-2 (SWN2; <a href="/entry/615670">615670</a>), <a href="#8" class="mim-tip-reference" title="Piotrowski, A., Xie, J., Liu, Y. F., Poplawski, A. B., Gomes, A. R., Madanecki, P., Fu, C., Crowley, M. R., Crossman, D. K., Armstrong, L., Babovic-Vuksanovic, D., Bergner, A., and 16 others. <strong>Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas.</strong> Nature Genet. 46: 182-187, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24362817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24362817</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24362817[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24362817">Piotrowski et al. (2014)</a> identified a germline heterozygous G-to-A transition in intron 2 of the LZTR1 gene (c.264-13G-A), predicted to result in premature termination (Lys89CysfsTer16) and a loss of function. The mutation was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project databases. Tumor tissue also carried the heterozygous LZTR1 mutation, and showed loss of heterozygosity (LOH) at chromosome 22q11, including both the LZTR1 and NF2 (<a href="/entry/607379">607379</a>) genes. In addition, the tumors carried a heterozygous somatic mutation in the NF2 gene. These findings were consistent with biallelic loss of function of both LZTR1 and NF2 in all tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24362817" 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 father and son with schwannomatosis-2 (SWN2; <a href="/entry/615670">615670</a>), <a href="#8" class="mim-tip-reference" title="Piotrowski, A., Xie, J., Liu, Y. F., Poplawski, A. B., Gomes, A. R., Madanecki, P., Fu, C., Crowley, M. R., Crossman, D. K., Armstrong, L., Babovic-Vuksanovic, D., Bergner, A., and 16 others. <strong>Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas.</strong> Nature Genet. 46: 182-187, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24362817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24362817</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24362817[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24362817">Piotrowski et al. (2014)</a> identified a germline heterozygous c.365C-T transition in exon 4 of the LZTR1 gene, resulting in a ser122-to-leu (S122L) substitution at a highly conserved residue in the second Kelch motif. The mutation was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project databases. Functional studies of the variant were not performed. Tumor tissue also carried the heterozygous LZTR1 mutation, and showed loss of heterozygosity (LOH) at chromosome 22q11, including both the LZTR1 and NF2 (<a href="/entry/607379">607379</a>) genes. In addition, the tumors carried a heterozygous somatic mutation in the NF2 gene. These findings were consistent with biallelic loss of function of both LZTR1 and NF2 in all tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24362817" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Steklov, M., Pandolfi, S., Baietti, M. F., Batiuk, A., Carai, P., Najm, P., Zhang, M., Jang, H., Renzi, F., Cai, Y., Asbagh, L. A., Pastor, T., and 13 others. <strong>Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination.</strong> Science 362: 1177-1182, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30442762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30442762</a>] [<a href="https://doi.org/10.1126/science.aap7607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30442762">Steklov et al. (2018)</a> found that LZTR1 Kelch domain mutants, including S122L, showed decreased binding to RAS in coimmunoprecipitation assays. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30442762" 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> rs587777178 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777178;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/rs587777178?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=rs587777178" 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=rs587777178" 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=RCV000087294 OR RCV001055087 OR RCV002415585 OR RCV004529908 OR RCV004776273 OR RCV005025171" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000087294, RCV001055087, RCV002415585, RCV004529908, RCV004776273, RCV005025171" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000087294...</a>
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<p>In a woman with schwannomatosis-2 (SWN2; <a href="/entry/615670">615670</a>), <a href="#8" class="mim-tip-reference" title="Piotrowski, A., Xie, J., Liu, Y. F., Poplawski, A. B., Gomes, A. R., Madanecki, P., Fu, C., Crowley, M. R., Crossman, D. K., Armstrong, L., Babovic-Vuksanovic, D., Bergner, A., and 16 others. <strong>Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas.</strong> Nature Genet. 46: 182-187, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24362817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24362817</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24362817[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24362817">Piotrowski et al. (2014)</a> identified a germline heterozygous c.2062C-T transition in exon 17 of the LZTR1 gene, resulting in an arg688-to-cys (R688C) substitution at a highly conserved residue in the BTB-II domain. The patient's unaffected father also carried this mutation, indicating incomplete penetrance. An unrelated 34-year-old woman with apparently sporadic disease also carried this mutation. The mutation was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project databases. Tumor tissue also carried the heterozygous LZTR1 mutation, and showed loss of heterozygosity (LOH) at chromosome 22q11, including both the LZTR1 and NF2 (<a href="/entry/607379">607379</a>) genes. In addition, the tumors carried a heterozygous somatic mutation in the NF2 gene. These findings were consistent with biallelic loss of function of both LZTR1 and NF2 in all tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24362817" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Steklov, M., Pandolfi, S., Baietti, M. F., Batiuk, A., Carai, P., Najm, P., Zhang, M., Jang, H., Renzi, F., Cai, Y., Asbagh, L. A., Pastor, T., and 13 others. <strong>Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination.</strong> Science 362: 1177-1182, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30442762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30442762</a>] [<a href="https://doi.org/10.1126/science.aap7607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30442762">Steklov et al. (2018)</a> found that R688C LZTR1 protein exhibited reduced binding to CUL3. On immunostaining, mutant protein showed diffuse cytoplasmic localization rather than the punctate endomembrane localization displayed by wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30442762" 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">rs587777613 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777613;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=rs587777613" 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=rs587777613" 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=RCV000133460 OR RCV000680837 OR RCV002433625 OR RCV003225720 OR RCV003388573 OR RCV005025221" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000133460, RCV000680837, RCV002433625, RCV003225720, RCV003388573, RCV005025221" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000133460...</a>
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<p>In a woman with schwannomatosis-2 (SWN2; <a href="/entry/615670">615670</a>), <a href="#8" class="mim-tip-reference" title="Piotrowski, A., Xie, J., Liu, Y. F., Poplawski, A. B., Gomes, A. R., Madanecki, P., Fu, C., Crowley, M. R., Crossman, D. K., Armstrong, L., Babovic-Vuksanovic, D., Bergner, A., and 16 others. <strong>Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas.</strong> Nature Genet. 46: 182-187, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24362817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24362817</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24362817[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24362817">Piotrowski et al. (2014)</a> identified a germline heterozygous 1-bp deletion (27delG) in exon 1 of the LZTR1 gene, resulting in a frameshift and premature termination (Gln10ArgfsTer15). The mutation was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project databases. Tumor tissue also carried the heterozygous LZTR1 mutation, and showed loss of heterozygosity (LOH) at chromosome 22q11, including both the LZTR1 and NF2 (<a href="/entry/607379">607379</a>) genes. In addition, the tumors carried a heterozygous somatic mutation in the NF2 gene. These findings were consistent with biallelic loss of function of both LZTR1 and NF2 in all tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24362817" 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">rs587777179 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777179;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=rs587777179" 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=rs587777179" 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=RCV000087295 OR RCV001379853 OR RCV002444559 OR RCV004783743" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000087295, RCV001379853, RCV002444559, RCV004783743" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000087295...</a>
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<p>In a father and 2 of his adult children with schwannomatosis-2 (SWN2; <a href="/entry/615670">615670</a>), <a href="#8" class="mim-tip-reference" title="Piotrowski, A., Xie, J., Liu, Y. F., Poplawski, A. B., Gomes, A. R., Madanecki, P., Fu, C., Crowley, M. R., Crossman, D. K., Armstrong, L., Babovic-Vuksanovic, D., Bergner, A., and 16 others. <strong>Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas.</strong> Nature Genet. 46: 182-187, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24362817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24362817</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24362817[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24362817">Piotrowski et al. (2014)</a> identified a germline heterozygous 4-bp deletion (c.2348_2351delCGCA) in exon 20 of the LZTR1 gene, resulting in a frameshift and premature termination (Thr783ArgfsTer5). The mutation was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project databases. Tumor tissue also carried the heterozygous LZTR1 mutation, and showed loss of heterozygosity (LOH) at chromosome 22q11, including both the LZTR1 and NF2 (<a href="/entry/607379">607379</a>) genes. In addition, the tumors carried a heterozygous somatic mutation in the NF2 gene. These findings were consistent with biallelic loss of function of both LZTR1 and NF2 in all tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24362817" 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> rs587777180 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777180;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/rs587777180?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=rs587777180" 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=rs587777180" 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=RCV000087296 OR RCV001260384 OR RCV001312780 OR RCV001813376 OR RCV002390252 OR RCV004815183 OR RCV005031596" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000087296, RCV001260384, RCV001312780, RCV001813376, RCV002390252, RCV004815183, RCV005031596" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000087296...</a>
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<p>In a father and his adult daughter with schwannomatosis-2 (SWN2; <a href="/entry/615670">615670</a>), <a href="#8" class="mim-tip-reference" title="Piotrowski, A., Xie, J., Liu, Y. F., Poplawski, A. B., Gomes, A. R., Madanecki, P., Fu, C., Crowley, M. R., Crossman, D. K., Armstrong, L., Babovic-Vuksanovic, D., Bergner, A., and 16 others. <strong>Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas.</strong> Nature Genet. 46: 182-187, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24362817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24362817</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24362817[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24362817">Piotrowski et al. (2014)</a> identified a germline heterozygous c.1397G-A transition in exon 13 of the LZTR1 gene, resulting in an arg466-to-gln (R466Q) substitution at a highly conserved residue in the BTB-I domain. The mutation was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project databases. Functional studies of the variant were not performed. Tumor tissue also carried the heterozygous LZTR1 mutation, and showed loss of heterozygosity (LOH) at chromosome 22q11, including both the LZTR1 and NF2 (<a href="/entry/607379">607379</a>) genes. In addition, the tumors carried a heterozygous somatic mutation in the NF2 gene. These findings were consistent with biallelic loss of function of both LZTR1 and NF2 in all tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24362817" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Steklov, M., Pandolfi, S., Baietti, M. F., Batiuk, A., Carai, P., Najm, P., Zhang, M., Jang, H., Renzi, F., Cai, Y., Asbagh, L. A., Pastor, T., and 13 others. <strong>Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination.</strong> Science 362: 1177-1182, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30442762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30442762</a>] [<a href="https://doi.org/10.1126/science.aap7607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30442762">Steklov et al. (2018)</a> found that R466Q LZTR1 protein exhibited reduced binding to CUL3. On immunostaining, mutant protein showed diffuse cytoplasmic localization rather than the punctate endomembrane localization displayed by wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30442762" 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> rs797045165 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797045165;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/rs797045165?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=rs797045165" 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=rs797045165" 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=RCV000191028 OR RCV000658480 OR RCV000763073 OR RCV002444774 OR RCV004530087 OR RCV004796089" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000191028, RCV000658480, RCV000763073, RCV002444774, RCV004530087, RCV004796089" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000191028...</a>
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<p>In 6 members of a Brazilian family (Br-F4) with Noonan syndrome-10 (NS10; <a href="/entry/616564">616564</a>), <a href="#11" class="mim-tip-reference" title="Yamamoto, G. L., Aguena, M., Gos, M., Hung, C., Pilch, J., Fahiminiya, S., Abramowicz, A., Cristian, I., Buscarilli, M., Naslavsky, M. S., Malaquias, A. C., Zatz, M., Bodamer, O., Majewski, J., Jorge, A. A. L., Pereira, A. C., Kim, C. A., Passos-Bueno, M. R., Bertola, D. R. <strong>Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome.</strong> J. Med. Genet. 52: 413-421, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25795793/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25795793</a>] [<a href="https://doi.org/10.1136/jmedgenet-2015-103018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25795793">Yamamoto et al. (2015)</a> identified a heterozygous c.850C-T transition (c.850C-T, NM_006767.3) in exon 9 of the LZTR1 gene, resulting in an arg284-to-cys (R284C) substitution in the KT4 domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the 1000 Genomes Project and Exome Sequencing Project databases and 609 Brazilian controls. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25795793" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Jacquinet, A., Bonnard, A., Capri, Y., Martin, D., Sadzot, B., Bianchi, E., Servais, L., Sacre, J.-P., Cave, H., Verloes, A. <strong>Oligo-astrocytoma in LZTR1-related Noonan syndrome.</strong> Europ. J. Med. Genet. 63: 103617, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30664951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30664951</a>] [<a href="https://doi.org/10.1016/j.ejmg.2019.01.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30664951">Jacquinet et al. (2020)</a> reported a 26-year-old male with NS10 who had inherited the R284C mutation from his affected mother. He developed an oligoastrocytoma at age 22 years that was resected but recurred as a ganglioblastoma at age 26 years. The patient had been treated with growth hormone for short stature between ages 15 and 17 years. Facial features of Noonan syndrome, kyphoscoliosis with gibbus, and pectus excavatum were present; cardiac malformation, cardiomyopathy, and hyperkeratosis were absent. <a href="#4" class="mim-tip-reference" title="Jacquinet, A., Bonnard, A., Capri, Y., Martin, D., Sadzot, B., Bianchi, E., Servais, L., Sacre, J.-P., Cave, H., Verloes, A. <strong>Oligo-astrocytoma in LZTR1-related Noonan syndrome.</strong> Europ. J. Med. Genet. 63: 103617, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30664951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30664951</a>] [<a href="https://doi.org/10.1016/j.ejmg.2019.01.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30664951">Jacquinet et al. (2020)</a> hypothesized that gliomas are a possible complication of LZTR1-related Noonan syndrome, and stated that their report supported a possible link between occurrence of a cerebral tumor in Noonan syndrome and treatment with growth hormone. In addition to the R284C mutation, the patient and his mother carried a mutation resulting in Charcot-Marie-Tooth disease type 1A (CMT1A; <a href="/entry/601097">601097</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30664951" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000191027 OR RCV000413889 OR RCV000763072 OR RCV001526613 OR RCV002381647 OR RCV003988835 OR RCV004576927 OR RCV004698786 OR RCV004734846" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000191027, RCV000413889, RCV000763072, RCV001526613, RCV002381647, RCV003988835, RCV004576927, RCV004698786, RCV004734846" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000191027...</a>
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<p>In 3 members of a Brazilian family (Br-F3) with Noonan syndrome-10 (NS10; <a href="/entry/616564">616564</a>), <a href="#11" class="mim-tip-reference" title="Yamamoto, G. L., Aguena, M., Gos, M., Hung, C., Pilch, J., Fahiminiya, S., Abramowicz, A., Cristian, I., Buscarilli, M., Naslavsky, M. S., Malaquias, A. C., Zatz, M., Bodamer, O., Majewski, J., Jorge, A. A. L., Pereira, A. C., Kim, C. A., Passos-Bueno, M. R., Bertola, D. R. <strong>Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome.</strong> J. Med. Genet. 52: 413-421, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25795793/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25795793</a>] [<a href="https://doi.org/10.1136/jmedgenet-2015-103018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25795793">Yamamoto et al. (2015)</a> identified a heterozygous c.742G-A transition (c.742G-A, NM_006767.3) in exon 8 of the LZTR1 gene, resulting in a gly248-to-arg (G248R) substitution in the KT4 domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the 1000 Genomes Project and Exome Sequencing Project databases and 609 Brazilian controls. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25795793" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Steklov, M., Pandolfi, S., Baietti, M. F., Batiuk, A., Carai, P., Najm, P., Zhang, M., Jang, H., Renzi, F., Cai, Y., Asbagh, L. A., Pastor, T., and 13 others. <strong>Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination.</strong> Science 362: 1177-1182, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30442762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30442762</a>] [<a href="https://doi.org/10.1126/science.aap7607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30442762">Steklov et al. (2018)</a> found that LZTR1 Kelch domain mutants, including G248R, showed decreased binding to RAS in coimmunoprecipitation assays. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30442762" 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 Polish mother and son (family Po-F1) with Noonan syndrome-10 (NS10; <a href="/entry/616564">616564</a>), <a href="#11" class="mim-tip-reference" title="Yamamoto, G. L., Aguena, M., Gos, M., Hung, C., Pilch, J., Fahiminiya, S., Abramowicz, A., Cristian, I., Buscarilli, M., Naslavsky, M. S., Malaquias, A. C., Zatz, M., Bodamer, O., Majewski, J., Jorge, A. A. L., Pereira, A. C., Kim, C. A., Passos-Bueno, M. R., Bertola, D. R. <strong>Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome.</strong> J. Med. Genet. 52: 413-421, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25795793/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25795793</a>] [<a href="https://doi.org/10.1136/jmedgenet-2015-103018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25795793">Yamamoto et al. (2015)</a> identified a heterozygous c.740G-A transition (c.740G-A, NM_006767.3) in exon 8 of the LZTR1 gene, resulting in a ser247-to-asn (S247N) substitution in the KT4 domain. Functional studies of the variant were not performed. The mother developed multiple schwannomas in her right arm, suggesting that the mutation resulted in a loss of function, as observed in schwannomatosis-2 (SWN2; <a href="/entry/615670">615670</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25795793" 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> rs150419186 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs150419186;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/rs150419186?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=rs150419186" 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=rs150419186" 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=RCV000735431 OR RCV000760481 OR RCV001330297 OR RCV002290002 OR RCV002360863 OR RCV004535887" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000735431, RCV000760481, RCV001330297, RCV002290002, RCV002360863, RCV004535887" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000735431...</a>
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<p>In a nonconsanguineous family of European origin (family 1) with 4 affected sibs with autosomal recessive Noonan syndrome (NS2; <a href="/entry/605275">605275</a>), <a href="#5" class="mim-tip-reference" title="Johnston, J. J., van der Smagt, J. J., Rosenfeld, J. A., Pagnamenta, A. T., Alswaid, A., Baker, E. H., Blair, E., Borck, G., Brinkmann, J., Craigen, W., Dung, V. C., Emrick, L., and 25 others. <strong>Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.</strong> Genet. Med. 20: 1175-1185, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29469822/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29469822</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29469822[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/gim.2017.249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29469822">Johnston et al. (2018)</a> reported compound heterozygosity for mutations in the LZTR1 gene: a paternally inherited C-to-T transition at nucleotide 628 (c.628C-T, NM_006767.3), resulting in substitution of a premature termination codon for arg210 (R210X), and a maternally inherited splice site mutation (c.2220-17C-A; <a href="#0011">600574.0011</a>). Parents had no dysmorphic features of Noonan syndrome. One affected sib developed acute lymphoblastic leukemia at age 5 years, which progressed to acute myeloblastic leukemia at 7 years and resulted in death at age 9 years. Several family members had subtle imaging findings consistent with schwannomas. The R210X mutation was seen in 21 of 281,548 alleles in gnomAD, never in homozygosity (<a href="#3" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 12/14/2018."None>Hamosh, 2018</a>). The splice site mutation produced a splice variant that retained intron 18, which predicted premature termination (Tyr741HisfsTer89). Sanger sequencing of a SNP in the LZTR1 gene showed cDNA skewing toward this transcript, suggesting moderate nonsense-mediated decay of the R210X-mutated transcript. The c.2220-17C-A mutation was seen in 2 of 281,760 alleles in gnomAD, never in homozygosity (December 14, 2018) (<a href="#3" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 12/14/2018."None>Hamosh, 2018</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29469822" 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> rs1249726034 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1249726034;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/rs1249726034?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=rs1249726034" 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=rs1249726034" 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=RCV000735430 OR RCV003465672" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000735430, RCV003465672" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000735430...</a>
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<p>For discussion of the c.2220-17C-A mutation (c.2220-17C-A, NM_006767.3) in the LZTR1 gene, resulting in retention of intron 18, frameshift, and premature termination of the protein, that was found in compound heterozygous state in 4 sibs with autosomal recessive Noonan syndrome (NS2; <a href="/entry/605275">605275</a>) by <a href="#5" class="mim-tip-reference" title="Johnston, J. J., van der Smagt, J. J., Rosenfeld, J. A., Pagnamenta, A. T., Alswaid, A., Baker, E. H., Blair, E., Borck, G., Brinkmann, J., Craigen, W., Dung, V. C., Emrick, L., and 25 others. <strong>Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.</strong> Genet. Med. 20: 1175-1185, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29469822/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29469822</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29469822[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/gim.2017.249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29469822">Johnston et al. (2018)</a>, see <a href="#0010">600574.0010</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29469822" 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> rs761685529 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs761685529;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/rs761685529?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=rs761685529" 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=rs761685529" 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=RCV000681140 OR RCV000735432 OR RCV002413779 OR RCV003336096 OR RCV003465362" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000681140, RCV000735432, RCV002413779, RCV003336096, RCV003465362" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000681140...</a>
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<p>In affected members of 4 families (2, 3, 10, and 11) with autosomal recessive Noonan syndrome (NS2; <a href="/entry/605275">605275</a>), <a href="#5" class="mim-tip-reference" title="Johnston, J. J., van der Smagt, J. J., Rosenfeld, J. A., Pagnamenta, A. T., Alswaid, A., Baker, E. H., Blair, E., Borck, G., Brinkmann, J., Craigen, W., Dung, V. C., Emrick, L., and 25 others. <strong>Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.</strong> Genet. Med. 20: 1175-1185, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29469822/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29469822</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29469822[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/gim.2017.249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29469822">Johnston et al. (2018)</a> identified a splice site mutation (c.1943-256C-T, NM_006767.3) in the LZTR1 gene. The mutation occurred 3 times in heterozygosity and once in homozygosity. RT-PCR data from lymphoblasts showed the c.1943-256C-T mutation caused retention of a 117-bp alternate exon that lies within intron 16 of LZTR1. The c.1943-256C-T mutation was seen in 11 of 178,598 alleles in gnomAD, never in homozygosity (December 14, 2018) (<a href="#3" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 12/14/2018."None>Hamosh, 2018</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29469822" 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> rs762834512 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs762834512;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/rs762834512?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=rs762834512" 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=rs762834512" 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=RCV000735433 OR RCV002442561 OR RCV002535430" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000735433, RCV002442561, RCV002535430" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000735433...</a>
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<p>In the proband of a family (7) with Noonan syndrome-2 (NS2; <a href="/entry/605275">605275</a>), <a href="#5" class="mim-tip-reference" title="Johnston, J. J., van der Smagt, J. J., Rosenfeld, J. A., Pagnamenta, A. T., Alswaid, A., Baker, E. H., Blair, E., Borck, G., Brinkmann, J., Craigen, W., Dung, V. C., Emrick, L., and 25 others. <strong>Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.</strong> Genet. Med. 20: 1175-1185, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29469822/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29469822</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29469822[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/gim.2017.249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29469822">Johnston et al. (2018)</a> identified compound heterozygosity for 2 missense mutations in the LZTR1 gene: the maternal allele carried a G-to-A transition at nucleotide 2264 (c.2264G-A, NM_006767.3) resulting in an arg-to-gln substitution at codon 755 (R755Q), and the paternal allele carried a C-to-G transversion at nucleotide 361 that resulted in a his121-to-asp (H121D) substitution. The proband had increased nuchal translucency prenatally, and his brother was born at 28 weeks' gestation with hydrops fetalis and died neonatally. <a href="#5" class="mim-tip-reference" title="Johnston, J. J., van der Smagt, J. J., Rosenfeld, J. A., Pagnamenta, A. T., Alswaid, A., Baker, E. H., Blair, E., Borck, G., Brinkmann, J., Craigen, W., Dung, V. C., Emrick, L., and 25 others. <strong>Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.</strong> Genet. Med. 20: 1175-1185, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29469822/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29469822</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29469822[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/gim.2017.249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29469822">Johnston et al. (2018)</a> reported that the H121D variant was not seen in gnomAD, and that the R755Q variant occurred in 1 of 246,052 alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29469822" 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">rs1569154492 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1569154492;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=rs1569154492" 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=rs1569154492" 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=RCV000735434 OR RCV003989594" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000735434, RCV003989594" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000735434...</a>
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<p>For discussion of the c.361C-G transversion (c.361C-G, NM_006767.3) in the ZTR1 gene, resulting in a his121-to-asp (H121D) substitution, that was found in compound heterozygous state in a proband with autosomal recessive Noonan syndrome (NS2; <a href="/entry/605275">605275</a>) by <a href="#5" class="mim-tip-reference" title="Johnston, J. J., van der Smagt, J. J., Rosenfeld, J. A., Pagnamenta, A. T., Alswaid, A., Baker, E. H., Blair, E., Borck, G., Brinkmann, J., Craigen, W., Dung, V. C., Emrick, L., and 25 others. <strong>Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.</strong> Genet. Med. 20: 1175-1185, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29469822/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29469822</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29469822[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/gim.2017.249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29469822">Johnston et al. (2018)</a>, see <a href="#0013">600574.0013</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29469822" 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/10.1126/science.aap8210" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.aav1444" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ejmg.2019.01.007" target="_blank">Full Text</a>]
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Johnston, J. J., van der Smagt, J. J., Rosenfeld, J. A., Pagnamenta, A. T., Alswaid, A., Baker, E. H., Blair, E., Borck, G., Brinkmann, J., Craigen, W., Dung, V. C., Emrick, L., and 25 others.
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<strong>Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.</strong>
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[<a href="https://doi.org/10.1038/gim.2017.249" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30442762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30442762</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30442762" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.aap7607" target="_blank">Full Text</a>]
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Umeki, I., Niihori, T., Abe, T., Kanno, S., Okamoto, N., Mizuno, S., Kurosawa, K., Nagasaki, K., Yoshida, M., Ohashi, H., Inoue, S., Matsubara, Y., Fujiwara, I., Kure, S., Aoki, Y.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30368668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30368668</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30368668" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00439-018-1951-7" target="_blank">Full Text</a>]
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Yamamoto, G. L., Aguena, M., Gos, M., Hung, C., Pilch, J., Fahiminiya, S., Abramowicz, A., Cristian, I., Buscarilli, M., Naslavsky, M. S., Malaquias, A. C., Zatz, M., Bodamer, O., Majewski, J., Jorge, A. A. L., Pereira, A. C., Kim, C. A., Passos-Bueno, M. R., Bertola, D. R.
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Ada Hamosh - updated : 11/03/2020
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Ada Hamosh - updated : 08/28/2019<br>Bao Lige - updated : 03/21/2019<br>Ada Hamosh - updated : 12/17/2018<br>Cassandra L. Kniffin - updated : 9/21/2015<br>Cassandra L. Kniffin - updated : 2/27/2014
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alopez : 11/03/2020<br>alopez : 08/28/2019<br>carol : 03/22/2019<br>mgross : 03/21/2019<br>alopez : 12/17/2018<br>carol : 09/23/2015<br>ckniffin : 9/21/2015<br>carol : 3/4/2014<br>mcolton : 2/28/2014<br>ckniffin : 2/27/2014<br>psherman : 10/20/1999<br>dkim : 7/2/1998<br>mark : 6/29/1995<br>mark : 6/1/1995
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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 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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<h3>
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<span class="mim-font">
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<strong>*</strong> 600574
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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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LEUCINE ZIPPER-LIKE TRANSCRIPTIONAL REGULATOR 1; LZTR1
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</span>
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</h3>
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<br />
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: LZTR1</em></strong>
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</span>
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</p>
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</div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 22q11.21
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Genomic coordinates <span class="small">(GRCh38)</span> : 22:20,982,297-20,999,032 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="3">
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<span class="mim-font">
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22q11.21
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</span>
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</td>
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<td>
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<span class="mim-font">
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{Schwannomatosis-2, susceptibility to}
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</td>
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<td>
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<span class="mim-font">
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615670
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Noonan syndrome 10
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</span>
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</td>
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<td>
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<span class="mim-font">
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616564
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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<tr>
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<td>
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<span class="mim-font">
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Noonan syndrome 2
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</span>
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</td>
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<td>
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<span class="mim-font">
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605275
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The LZTR1 gene encodes a protein that belongs to a functionally diverse superfamily of BTB/POZ (broad complex, tramtrack, and bric-a-brac/poxvirus and zinc finger) proteins. BTB-containing proteins control fundamental cellular processes, ranging from the regulation of chromatin conformation to the cell cycle (summary by Piotrowski et al., 2014). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By a microdissection and microcloning method, Kurahashi et al. (1995) constructed a specific plasmid library from the 22q11 region which is commonly deleted in the DiGeorge syndrome (DGS; 188400). Dosage analysis proved that 3 of 144 randomly selected microclones detected hemizygosity in 2 patients with DGS. They then obtained 2 cosmid contigs corresponding to the microclones and using 1 of the cosmids of 1 of the contigs identified a 4.3-kb cDNA from a fetal brain cDNA library. Sequence analysis of the cDNA revealed an open reading frame encoding 552 amino acids that had several characteristics of DNA-binding proteins. The gene, designated LZTR1 (for leucine-zipper-like transcriptional regulator-1) by them, was transcribed in several essential fetal organs and proved to be hemizygously deleted in 7 of 8 DGS patients or its variants. Although LZTR1 did not locate in the shortest region of overlap of DGS, several of its structural characteristics identified it as a transcriptional regulator, suggesting that it plays a crucial role in embryogenesis and that haploinsufficiency of this gene may be partly responsible for the developmental abnormalities of DGS. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using immunoprecipitation of endogenous LZTR1 followed by Western blotting, Umeki et al. (2019) showed that LZTR1 bound to the RAF1 (164760)-SHOC2 (602775)-PPP1CB (600590) complex. Mutations in these genes cause Noonan syndrome or Noonan-like phenotypes. Cells transfected with siRNA against LZTR1 exhibited decreased levels of RAF1 phosphorylated at ser259. </p><p>By trapping LZTR1 complexes from intact mammalian cells, Steklov et al. (2018) identified the guanosine triphosphatase RAS (see 190020) as a substrate for the LZTR1-CUL3 complex. Ubiquitome analysis showed that loss of Lztr1 abrogated Ras ubiquitination at lysine-170. LZTR1-mediated ubiquitination inhibited RAS signaling by attenuating its association with the membrane. </p><p>Bigenzahn et al. (2018) found that knockdown of the Drosophila LZTR1 ortholog CG3711 resulted in a Ras-dependent gain-of-function phenotype. Endogenous human LZTR1 associates with the main RAS isoforms. Inactivation of LZTR1 led to decreased ubiquitination and enhanced plasma membrane localization of endogenous KRAS (190070). Bigenzahn et al. (2018) proposed that LZTR1 acts as a conserved regulator of RAS ubiquitination and MAPK pathway activation. LZTR1 disease mutations failed to revert loss-of-function phenotypes. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The LZTR1 gene maps to chromosome 22q11 (Kurahashi et al., 1995). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Schwannomatosis 2</em></strong></p><p>
|
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In 16 of 20 probands with schwannomatosis-2 (SWN2; 615670), Piotrowski et al. (2014) identified 15 different germline heterozygous mutations in the LZTR1 gene (see, e.g., 600574.0001-600574.0006). There were 6 truncating mutations, 1 in-frame splice site mutation, 1 deletion affecting a splice site, and 7 missense mutations at highly conserved residues. All schwannomas studied also carried the heterozygous LZTR1 mutation, and all showed loss of heterozygosity (LOH) at chromosome 22q11, including the LZTR1, SMARCB1 (601607), and NF2 (607379) genes. In addition, all tumors from all patients carried a heterozygous somatic mutation in the NF2 gene. These findings were consistent with biallelic loss of function of both LZTR1 and NF2 in all tumors. Functional studies of the variants were not performed. Piotrowski et al. (2014) characterized the pathogenesis of tumor development as resulting from 3 mutational events: a germline LZTR1 mutation (E1), a deletion of 22q that includes the LZTR1 and NF2 genes (E2), and a somatic NF2 mutation (E3). None of the patients or tumors carried a SMARCB1 mutation. The germline mutations segregated with the disorder in all available affected first-degree relatives, although 4 asymptomatic parents also carried the mutation, indicating incomplete penetrance. The findings suggested that loss of LZTR1 function can predispose to the development of autosomal dominant multiple schwannomas, thus implicating LZTR1 as a tumor suppressor gene. </p><p><strong><em>Noonan Syndrome 10</em></strong></p><p>
|
|
In affected members of 5 families with Noonan syndrome-10 (NS10; 616564), Yamamoto et al. (2015) identified 5 different heterozygous missense mutations in the LZTR1 gene (see, e.g., 600574.0007-600574.0009). All of the mutations occurred in the Kelch (KT) domains, but functional studies of the variants were not performed. Mutations in 4 of the families were found by whole-exome sequencing of a cohort of 50 Brazilian patients with Noonan syndrome; the fifth family was of Polish origin. </p><p>Umeki et al. (2019) reported 6 NS10 patients with heterozygous mutations in LZTR1. All patients had cardiac defects; other features were more variable. </p><p><strong><em>Noonan Syndrome 2</em></strong></p><p>
|
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Johnston et al. (2018) reported 17 mutations in 12 families with autosomal recessive Noonan syndrome (NS2; 605275). These included missense, nonsense, frameshift, and splice site mutations that occurred in homozygosity or compound heterozygosity. All parents were heterozygous and unaffected. </p><p>Umeki et al. (2019) reported 1 NS2 patient with compound heterozygous mutations in the LZTR1 gene as well as 6 NS10 patients with heterozygous mutations in LZTR1. All patients had cardiac defects and 71%, including the NS2 patient, had hypertrophic cardiomyopathy. Other features were more variable. The patient with NS2 inherited each mutation from one of her unaffected parents. </p><p><strong><em>Functional Studies of LZTR1 Mutations</em></strong></p><p>
|
|
Using transfected COS-1 and HEK293T cells, Motta et al. (2019) found that the NS-causing dominant mutations in LZTR1 did not impact protein stability or Golgi localization, but they enhanced stimulus-dependent RAS-MAPK signaling. In contrast, NS-causing recessive mutations in LZTR1 caused loss of function by affecting either protein stability or Golgi localization, but they had no impact on RAS-MAPK signaling. Coimmunoprecipitation analysis showed that NS-causing dominant mutations in LZTR1 did not affect BTB domain-mediated binding to CUL3 (603136). Structural analysis suggested that NS-causing dominant mutations in LZTR1 affected the substrate-binding Kelch domain of LZTR1, which mediates binding of substrate to the CUL3-RING ubiquitin ligase complex to promote substrate ubiquitination. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Steklov et al. (2018) found that LZTR1 haploinsufficiency in mice recapitulated Noonan syndrome phenotypes, whereas LZTR1 loss in Schwann cells drove differentiation and proliferation. Loss of Lztr1 was lethal between embryonic day embryonic day 17.5 and birth. Lztr1 +/- male mice exhibited decreased weight and facial dysmorphia. Lztr1 +/- mice, both male and female, displayed heart malformations, including decreased left ventricular systolic function, increased diastolic dimensions, eccentric hypertrophy, increased cardiomyocyte area, and reduced longevity. </p><p>Castel et al. (2019) used an isogenic germline knockin mouse model to study the effects of RIT1 (609591) mutation at the organismal level, which resulted in a phenotype resembling Noonan syndrome. By mass spectrometry, Castel et al. (2019) detected a RIT1 interactor, LZTR1, that acts as an adaptor for protein degradation. Pathogenic mutations affecting either RIT1 or LZTR1 resulted in incomplete degradation of RIT1. This led to RIT1 accumulation and dysregulated growth factor signaling responses. Castel et al. (2019) concluded that their results highlighted a mechanism of pathogenesis that relies on impaired protein degradation of the Ras GTPase RIT1. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>14 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 SCHWANNOMATOSIS 2</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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LZTR1, IVS2AS, G-A, -13
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<br />
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SNP: rs587777176,
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gnomAD: rs587777176,
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ClinVar: RCV000087292, RCV001291541, RCV002426650, RCV002498472, RCV003126498, RCV004700409, RCV004786368
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a father and 2 of his adult children with schwannomatosis-2 (SWN2; 615670), Piotrowski et al. (2014) identified a germline heterozygous G-to-A transition in intron 2 of the LZTR1 gene (c.264-13G-A), predicted to result in premature termination (Lys89CysfsTer16) and a loss of function. The mutation was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project databases. Tumor tissue also carried the heterozygous LZTR1 mutation, and showed loss of heterozygosity (LOH) at chromosome 22q11, including both the LZTR1 and NF2 (607379) genes. In addition, the tumors carried a heterozygous somatic mutation in the NF2 gene. These findings were consistent with biallelic loss of function of both LZTR1 and NF2 in all tumors. </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>.0002 SCHWANNOMATOSIS 2</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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LZTR1, SER122LEU
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<br />
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SNP: rs587777177,
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gnomAD: rs587777177,
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ClinVar: RCV000087293, RCV001200448, RCV002453416, RCV003315228, RCV004529907, RCV004786369
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a father and son with schwannomatosis-2 (SWN2; 615670), Piotrowski et al. (2014) identified a germline heterozygous c.365C-T transition in exon 4 of the LZTR1 gene, resulting in a ser122-to-leu (S122L) substitution at a highly conserved residue in the second Kelch motif. The mutation was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project databases. Functional studies of the variant were not performed. Tumor tissue also carried the heterozygous LZTR1 mutation, and showed loss of heterozygosity (LOH) at chromosome 22q11, including both the LZTR1 and NF2 (607379) genes. In addition, the tumors carried a heterozygous somatic mutation in the NF2 gene. These findings were consistent with biallelic loss of function of both LZTR1 and NF2 in all tumors. </p><p>Steklov et al. (2018) found that LZTR1 Kelch domain mutants, including S122L, showed decreased binding to RAS in coimmunoprecipitation assays. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 SCHWANNOMATOSIS 2</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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LZTR1, ARG688CYS
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<br />
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SNP: rs587777178,
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gnomAD: rs587777178,
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ClinVar: RCV000087294, RCV001055087, RCV002415585, RCV004529908, RCV004776273, RCV005025171
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a woman with schwannomatosis-2 (SWN2; 615670), Piotrowski et al. (2014) identified a germline heterozygous c.2062C-T transition in exon 17 of the LZTR1 gene, resulting in an arg688-to-cys (R688C) substitution at a highly conserved residue in the BTB-II domain. The patient's unaffected father also carried this mutation, indicating incomplete penetrance. An unrelated 34-year-old woman with apparently sporadic disease also carried this mutation. The mutation was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project databases. Tumor tissue also carried the heterozygous LZTR1 mutation, and showed loss of heterozygosity (LOH) at chromosome 22q11, including both the LZTR1 and NF2 (607379) genes. In addition, the tumors carried a heterozygous somatic mutation in the NF2 gene. These findings were consistent with biallelic loss of function of both LZTR1 and NF2 in all tumors. </p><p>Steklov et al. (2018) found that R688C LZTR1 protein exhibited reduced binding to CUL3. On immunostaining, mutant protein showed diffuse cytoplasmic localization rather than the punctate endomembrane localization displayed by wildtype. </p>
|
|
</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 SCHWANNOMATOSIS 2</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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LZTR1, 1-BP DEL, 27G
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<br />
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SNP: rs587777613,
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ClinVar: RCV000133460, RCV000680837, RCV002433625, RCV003225720, RCV003388573, RCV005025221
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a woman with schwannomatosis-2 (SWN2; 615670), Piotrowski et al. (2014) identified a germline heterozygous 1-bp deletion (27delG) in exon 1 of the LZTR1 gene, resulting in a frameshift and premature termination (Gln10ArgfsTer15). The mutation was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project databases. Tumor tissue also carried the heterozygous LZTR1 mutation, and showed loss of heterozygosity (LOH) at chromosome 22q11, including both the LZTR1 and NF2 (607379) genes. In addition, the tumors carried a heterozygous somatic mutation in the NF2 gene. These findings were consistent with biallelic loss of function of both LZTR1 and NF2 in all tumors. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 SCHWANNOMATOSIS 2</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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LZTR1, 4-BP DEL, 2348CGCA
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<br />
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SNP: rs587777179,
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ClinVar: RCV000087295, RCV001379853, RCV002444559, RCV004783743
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a father and 2 of his adult children with schwannomatosis-2 (SWN2; 615670), Piotrowski et al. (2014) identified a germline heterozygous 4-bp deletion (c.2348_2351delCGCA) in exon 20 of the LZTR1 gene, resulting in a frameshift and premature termination (Thr783ArgfsTer5). The mutation was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project databases. Tumor tissue also carried the heterozygous LZTR1 mutation, and showed loss of heterozygosity (LOH) at chromosome 22q11, including both the LZTR1 and NF2 (607379) genes. In addition, the tumors carried a heterozygous somatic mutation in the NF2 gene. These findings were consistent with biallelic loss of function of both LZTR1 and NF2 in all tumors. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0006 SCHWANNOMATOSIS 2</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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LZTR1, ARG466GLN
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<br />
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SNP: rs587777180,
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gnomAD: rs587777180,
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ClinVar: RCV000087296, RCV001260384, RCV001312780, RCV001813376, RCV002390252, RCV004815183, RCV005031596
|
|
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|
</span>
|
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a father and his adult daughter with schwannomatosis-2 (SWN2; 615670), Piotrowski et al. (2014) identified a germline heterozygous c.1397G-A transition in exon 13 of the LZTR1 gene, resulting in an arg466-to-gln (R466Q) substitution at a highly conserved residue in the BTB-I domain. The mutation was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Sequencing Project databases. Functional studies of the variant were not performed. Tumor tissue also carried the heterozygous LZTR1 mutation, and showed loss of heterozygosity (LOH) at chromosome 22q11, including both the LZTR1 and NF2 (607379) genes. In addition, the tumors carried a heterozygous somatic mutation in the NF2 gene. These findings were consistent with biallelic loss of function of both LZTR1 and NF2 in all tumors. </p><p>Steklov et al. (2018) found that R466Q LZTR1 protein exhibited reduced binding to CUL3. On immunostaining, mutant protein showed diffuse cytoplasmic localization rather than the punctate endomembrane localization displayed by wildtype. </p>
|
|
</span>
|
|
</div>
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<div>
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|
<br />
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|
</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 NOONAN SYNDROME 10</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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LZTR1, ARG284CYS
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<br />
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SNP: rs797045165,
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|
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gnomAD: rs797045165,
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|
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|
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ClinVar: RCV000191028, RCV000658480, RCV000763073, RCV002444774, RCV004530087, RCV004796089
|
|
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|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 6 members of a Brazilian family (Br-F4) with Noonan syndrome-10 (NS10; 616564), Yamamoto et al. (2015) identified a heterozygous c.850C-T transition (c.850C-T, NM_006767.3) in exon 9 of the LZTR1 gene, resulting in an arg284-to-cys (R284C) substitution in the KT4 domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the 1000 Genomes Project and Exome Sequencing Project databases and 609 Brazilian controls. Functional studies of the variant were not performed. </p><p>Jacquinet et al. (2020) reported a 26-year-old male with NS10 who had inherited the R284C mutation from his affected mother. He developed an oligoastrocytoma at age 22 years that was resected but recurred as a ganglioblastoma at age 26 years. The patient had been treated with growth hormone for short stature between ages 15 and 17 years. Facial features of Noonan syndrome, kyphoscoliosis with gibbus, and pectus excavatum were present; cardiac malformation, cardiomyopathy, and hyperkeratosis were absent. Jacquinet et al. (2020) hypothesized that gliomas are a possible complication of LZTR1-related Noonan syndrome, and stated that their report supported a possible link between occurrence of a cerebral tumor in Noonan syndrome and treatment with growth hormone. In addition to the R284C mutation, the patient and his mother carried a mutation resulting in Charcot-Marie-Tooth disease type 1A (CMT1A; 601097). </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 NOONAN SYNDROME 10</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
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|
|
<div>
|
|
<span class="mim-text-font">
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|
|
|
LZTR1, GLY248ARG
|
|
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|
|
<br />
|
|
|
|
SNP: rs869320686,
|
|
|
|
|
|
gnomAD: rs869320686,
|
|
|
|
|
|
ClinVar: RCV000191027, RCV000413889, RCV000763072, RCV001526613, RCV002381647, RCV003988835, RCV004576927, RCV004698786, RCV004734846
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 members of a Brazilian family (Br-F3) with Noonan syndrome-10 (NS10; 616564), Yamamoto et al. (2015) identified a heterozygous c.742G-A transition (c.742G-A, NM_006767.3) in exon 8 of the LZTR1 gene, resulting in a gly248-to-arg (G248R) substitution in the KT4 domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the 1000 Genomes Project and Exome Sequencing Project databases and 609 Brazilian controls. Functional studies of the variant were not performed. </p><p>Steklov et al. (2018) found that LZTR1 Kelch domain mutants, including G248R, showed decreased binding to RAS in coimmunoprecipitation assays. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 NOONAN SYNDROME 10</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LZTR1, SER247ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs797045166,
|
|
|
|
|
|
|
|
ClinVar: RCV000191029
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Polish mother and son (family Po-F1) with Noonan syndrome-10 (NS10; 616564), Yamamoto et al. (2015) identified a heterozygous c.740G-A transition (c.740G-A, NM_006767.3) in exon 8 of the LZTR1 gene, resulting in a ser247-to-asn (S247N) substitution in the KT4 domain. Functional studies of the variant were not performed. The mother developed multiple schwannomas in her right arm, suggesting that the mutation resulted in a loss of function, as observed in schwannomatosis-2 (SWN2; 615670). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 NOONAN SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LZTR1, ARG210TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs150419186,
|
|
|
|
|
|
gnomAD: rs150419186,
|
|
|
|
|
|
ClinVar: RCV000735431, RCV000760481, RCV001330297, RCV002290002, RCV002360863, RCV004535887
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a nonconsanguineous family of European origin (family 1) with 4 affected sibs with autosomal recessive Noonan syndrome (NS2; 605275), Johnston et al. (2018) reported compound heterozygosity for mutations in the LZTR1 gene: a paternally inherited C-to-T transition at nucleotide 628 (c.628C-T, NM_006767.3), resulting in substitution of a premature termination codon for arg210 (R210X), and a maternally inherited splice site mutation (c.2220-17C-A; 600574.0011). Parents had no dysmorphic features of Noonan syndrome. One affected sib developed acute lymphoblastic leukemia at age 5 years, which progressed to acute myeloblastic leukemia at 7 years and resulted in death at age 9 years. Several family members had subtle imaging findings consistent with schwannomas. The R210X mutation was seen in 21 of 281,548 alleles in gnomAD, never in homozygosity (Hamosh, 2018). The splice site mutation produced a splice variant that retained intron 18, which predicted premature termination (Tyr741HisfsTer89). Sanger sequencing of a SNP in the LZTR1 gene showed cDNA skewing toward this transcript, suggesting moderate nonsense-mediated decay of the R210X-mutated transcript. The c.2220-17C-A mutation was seen in 2 of 281,760 alleles in gnomAD, never in homozygosity (December 14, 2018) (Hamosh, 2018). </p>
|
|
</span>
|
|
</div>
|
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|
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|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 NOONAN SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LZTR1, IVS18, C-A, -17
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1249726034,
|
|
|
|
|
|
gnomAD: rs1249726034,
|
|
|
|
|
|
ClinVar: RCV000735430, RCV003465672
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.2220-17C-A mutation (c.2220-17C-A, NM_006767.3) in the LZTR1 gene, resulting in retention of intron 18, frameshift, and premature termination of the protein, that was found in compound heterozygous state in 4 sibs with autosomal recessive Noonan syndrome (NS2; 605275) by Johnston et al. (2018), see 600574.0010. </p>
|
|
</span>
|
|
</div>
|
|
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|
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|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 NOONAN SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LZTR1, 1943-256C-T
|
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|
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<br />
|
|
|
|
SNP: rs761685529,
|
|
|
|
|
|
gnomAD: rs761685529,
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|
|
|
|
|
ClinVar: RCV000681140, RCV000735432, RCV002413779, RCV003336096, RCV003465362
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of 4 families (2, 3, 10, and 11) with autosomal recessive Noonan syndrome (NS2; 605275), Johnston et al. (2018) identified a splice site mutation (c.1943-256C-T, NM_006767.3) in the LZTR1 gene. The mutation occurred 3 times in heterozygosity and once in homozygosity. RT-PCR data from lymphoblasts showed the c.1943-256C-T mutation caused retention of a 117-bp alternate exon that lies within intron 16 of LZTR1. The c.1943-256C-T mutation was seen in 11 of 178,598 alleles in gnomAD, never in homozygosity (December 14, 2018) (Hamosh, 2018). </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 NOONAN SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
LZTR1, ARG755GLN
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|
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|
<br />
|
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|
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SNP: rs762834512,
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|
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gnomAD: rs762834512,
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|
|
|
|
|
ClinVar: RCV000735433, RCV002442561, RCV002535430
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In the proband of a family (7) with Noonan syndrome-2 (NS2; 605275), Johnston et al. (2018) identified compound heterozygosity for 2 missense mutations in the LZTR1 gene: the maternal allele carried a G-to-A transition at nucleotide 2264 (c.2264G-A, NM_006767.3) resulting in an arg-to-gln substitution at codon 755 (R755Q), and the paternal allele carried a C-to-G transversion at nucleotide 361 that resulted in a his121-to-asp (H121D) substitution. The proband had increased nuchal translucency prenatally, and his brother was born at 28 weeks' gestation with hydrops fetalis and died neonatally. Johnston et al. (2018) reported that the H121D variant was not seen in gnomAD, and that the R755Q variant occurred in 1 of 246,052 alleles. </p>
|
|
</span>
|
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</div>
|
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<div>
|
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<br />
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</div>
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</div>
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<div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 NOONAN SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
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|
LZTR1, HIS121ASP
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<br />
|
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|
|
SNP: rs1569154492,
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|
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|
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ClinVar: RCV000735434, RCV003989594
|
|
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|
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</span>
|
|
</div>
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.361C-G transversion (c.361C-G, NM_006767.3) in the ZTR1 gene, resulting in a his121-to-asp (H121D) substitution, that was found in compound heterozygous state in a proband with autosomal recessive Noonan syndrome (NS2; 605275) by Johnston et al. (2018), see 600574.0013. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
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</div>
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</div>
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</div>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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<strong>LZTR1 is a regulator of RAS ubiquitination and signaling.</strong>
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Castel, P., Cheng, A., Cuevas-Navarro, A., Everman, D. B., Papageorge, A. G., Simanshu, D. K., Tankka, A., Galeas, J., Urisman, A., McCormick, F.
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<p class="mim-text-font">
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Hamosh, A.
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<strong>Personal Communication.</strong>
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Jacquinet, A., Bonnard, A., Capri, Y., Martin, D., Sadzot, B., Bianchi, E., Servais, L., Sacre, J.-P., Cave, H., Verloes, A.
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<strong>Oligo-astrocytoma in LZTR1-related Noonan syndrome.</strong>
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Johnston, J. J., van der Smagt, J. J., Rosenfeld, J. A., Pagnamenta, A. T., Alswaid, A., Baker, E. H., Blair, E., Borck, G., Brinkmann, J., Craigen, W., Dung, V. C., Emrick, L., and 25 others.
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<strong>Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.</strong>
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Kurahashi, H., Akagi, K., Inazawa, J., Ohta, T., Niikawa, N., Kayatani, F., Sano, T., Okada, S., Nishisho, I.
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<strong>Isolation and characterization of a novel gene deleted in DiGeorge syndrome.</strong>
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Motta, M., Fidan, M., Bellacchio, E., Pantaleoni, F., Schneider-Heieck, K., Coppola, S., Borck, G., Salviati, L., Zenker, M., Cirstea, I. C., Tartaglia, M.
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<strong>Dominant Noonan syndrome-causing LZTR1 mutations specifically affect the Kelch domain substrate-recognition surface and enhance RAS-MAPK signaling.</strong>
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Piotrowski, A., Xie, J., Liu, Y. F., Poplawski, A. B., Gomes, A. R., Madanecki, P., Fu, C., Crowley, M. R., Crossman, D. K., Armstrong, L., Babovic-Vuksanovic, D., Bergner, A., and 16 others.
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<strong>Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas.</strong>
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Nature Genet. 46: 182-187, 2014.
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[PubMed: 24362817]
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[Full Text: https://doi.org/10.1038/ng.2855]
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Steklov, M., Pandolfi, S., Baietti, M. F., Batiuk, A., Carai, P., Najm, P., Zhang, M., Jang, H., Renzi, F., Cai, Y., Asbagh, L. A., Pastor, T., and 13 others.
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<strong>Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination.</strong>
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Science 362: 1177-1182, 2018.
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[PubMed: 30442762]
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[Full Text: https://doi.org/10.1126/science.aap7607]
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Umeki, I., Niihori, T., Abe, T., Kanno, S., Okamoto, N., Mizuno, S., Kurosawa, K., Nagasaki, K., Yoshida, M., Ohashi, H., Inoue, S., Matsubara, Y., Fujiwara, I., Kure, S., Aoki, Y.
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<strong>Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes.</strong>
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Hum. Genet. 138: 21-35, 2019.
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[PubMed: 30368668]
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[Full Text: https://doi.org/10.1007/s00439-018-1951-7]
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Yamamoto, G. L., Aguena, M., Gos, M., Hung, C., Pilch, J., Fahiminiya, S., Abramowicz, A., Cristian, I., Buscarilli, M., Naslavsky, M. S., Malaquias, A. C., Zatz, M., Bodamer, O., Majewski, J., Jorge, A. A. L., Pereira, A. C., Kim, C. A., Passos-Bueno, M. R., Bertola, D. R.
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<strong>Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome.</strong>
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J. Med. Genet. 52: 413-421, 2015.
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[PubMed: 25795793]
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[Full Text: https://doi.org/10.1136/jmedgenet-2015-103018]
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Ada Hamosh - updated : 11/03/2020<br>Ada Hamosh - updated : 08/28/2019<br>Bao Lige - updated : 03/21/2019<br>Ada Hamosh - updated : 12/17/2018<br>Cassandra L. Kniffin - updated : 9/21/2015<br>Cassandra L. Kniffin - updated : 2/27/2014
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<span class="mim-text-font">
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Victor A. McKusick : 6/1/1995
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