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Entry
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- *607072 - NPR2-LIKE PROTEIN, GATOR1 COMPLEX SUBUNIT; NPRL2
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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">*607072</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<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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<a href="#geneStructure">Gene Structure</a>
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/607072">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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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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<div 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="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=ENSG00000114388;t=ENST00000232501" 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=10641" 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=607072" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<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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</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=ENSG00000114388;t=ENST00000232501" 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_006545,XM_011533288,XM_017005556,XM_047447310,XM_047447311,XM_047447312,XM_047447314" 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_006545" 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=607072" 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=06147&isoform_id=06147_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/NPRL2" 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/2340095,2935585,3688795,18314624,34785137,47117604,49457023,50592992,119585510,119585511,119585512,119585513,119585514,119585515,119585516,158257824,767922144,1034630749,2217341420,2217341423,2217341425,2217341428,2462586548,2462586550,2462586552,2462586554,2462586556,2624363686,2624363688,2624363690" 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/Q8WTW4" 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=10641" 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=ENSG00000114388;t=ENST00000232501" 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=NPRL2" 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=NPRL2" 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+10641" 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/NPRL2" 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:10641" 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/10641" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr3&hgg_gene=ENST00000232501.8&hgg_start=50347330&hgg_end=50350775&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:24969" 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/nprl2" 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=607072[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=607072[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000114388" 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.gwascentral.org/search?q=NPRL2" 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=NPRL2" 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=NPRL2&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/PA165697981" 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:24969" 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/FBgn0030800.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:1914482" 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/NPRL2#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:1914482" 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/10641/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=10641" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00018635;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-060825-93" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:10641" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=NPRL2&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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607072
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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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NPR2-LIKE PROTEIN, GATOR1 COMPLEX SUBUNIT; NPRL2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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NPR2, S. CEREVISIAE, HOMOLOG OF; NPR2<br />
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NPR2L<br />
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TUMOR SUPPRESSOR CANDIDATE 4; TUSC4
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=NPRL2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">NPRL2</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/3/342?start=-3&limit=10&highlight=342">3p21.31</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:50347330-50350775&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">3:50,347,330-50,350,775</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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</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="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/3/342?start=-3&limit=10&highlight=342">
|
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3p21.31
|
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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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Epilepsy, familial focal, with variable foci 2
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/617116"> 617116 </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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</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/607072" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/607072" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</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="text" class="mim-anchor"></a>
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<h4>
|
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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<p>The NPRL2 gene encodes a subunit of the GATOR1 complex, which regulates the mTORC1 (see <a href="/entry/601231">601231</a>) signaling pathway. Other GATOR1 subunits include DEPDC5 (<a href="/entry/614191">614191</a>) and NPRL3 (<a href="/entry/600928">600928</a>) (summary by <a href="#4" class="mim-tip-reference" title="Ricos, M. G., Hodgson, B. L., Pippucci, T., Saidin, A., Ong, Y. S., Heron, S. E., Licchetta, L., Bisulli, F., Bayly, M. A., Hughes, J., Baldassari, S., Palombo, F., and 11 others. <strong>Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy.</strong> Ann. Neurol. 79: 120-131, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26505888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26505888</a>] [<a href="https://doi.org/10.1002/ana.24547" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26505888">Ricos et al., 2016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26505888" 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 physical cloning methodologies and bioinformatic computational analyses, <a href="#3" class="mim-tip-reference" title="Lerman, M. I., Minna, J. D. <strong>The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes.</strong> Cancer Res. 60: 6116-6133, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11085536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11085536</a>]" pmid="11085536">Lerman and Minna (2000)</a> identified a number of genes, including NPR2L, which they called NPRL2, in a region of chromosome 3p21.3 that is associated with a putative lung cancer tumor suppressor gene. The deduced 380-amino acid conserved soluble protein, which is 97% identical to the mouse protein and orthologous to the yeast nitrogen permease gene Npr2, contains a bipartite nuclear localization signal and a granulin protein-binding domain. The authors identified multiple NPRL2 splice variants. Northern blot analysis revealed expression of a 1.5-kb transcript that was most abundant in skeletal muscle, followed by brain, liver, and pancreas, with lower amounts in lung, kidney, placenta, and heart. NPRL2 was expressed in most lung cancer cell lines tested. Mutations, including stop mutations, were found in approximately 5% of cell lines tested, but none of the genes identified in the search had a high frequency of mutations. <a href="#3" class="mim-tip-reference" title="Lerman, M. I., Minna, J. D. <strong>The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes.</strong> Cancer Res. 60: 6116-6133, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11085536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11085536</a>]" pmid="11085536">Lerman and Minna (2000)</a> proposed that NPRL2 is a candidate for functional tumor suppressor gene studies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11085536" 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="Ricos, M. G., Hodgson, B. L., Pippucci, T., Saidin, A., Ong, Y. S., Heron, S. E., Licchetta, L., Bisulli, F., Bayly, M. A., Hughes, J., Baldassari, S., Palombo, F., and 11 others. <strong>Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy.</strong> Ann. Neurol. 79: 120-131, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26505888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26505888</a>] [<a href="https://doi.org/10.1002/ana.24547" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26505888">Ricos et al. (2016)</a> found expression of the NPRL3 gene in all human brain regions analyzed, including frontal, temporal, parietal, and occipital lobes. A similar pattern of expression was found in both embryonic and adult mouse brain. All 3 genes in the GATOR1 complex showed a striking similarity in tissue distribution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26505888" 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 genomic sequence analysis, <a href="#3" class="mim-tip-reference" title="Lerman, M. I., Minna, J. D. <strong>The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes.</strong> Cancer Res. 60: 6116-6133, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11085536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11085536</a>]" pmid="11085536">Lerman and Minna (2000)</a> determined that the NPRL2 gene contains 11 exons and spans 3.3 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11085536" 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="#5" class="mim-tip-reference" title="Shen, K., Huang, R. K., Brignole, E. J., Condon, K. J., Valenstein, M. L., Chantranupong, L., Bomaliyamu, A., Choe, A., Hong, C., Yu, Z., Sabatini, D. M. <strong>Architecture of the human GATOR1 and GATOR1-Rag GTPases complexes.</strong> Nature 556: 64-69, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29590090/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29590090</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29590090[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/nature26158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29590090">Shen et al. (2018)</a> used cryoelectron microscopy to solve structures of GATOR1 and GATOR1-RAG GTPases complexes. GATOR1 adopts an extended architecture with a cavity in the middle; NPRL2 links DEPDC5 and NPRL3, and DEPDC5 contacts the RAG GTPase heterodimer. Biochemical analyses revealed that this GATOR1-RAG GTPases structure is inhibitory, and that at least 2 binding modes must exist between the RAG GTPases and GATOR1. Direct interaction of DEPDC5 with RAGA (<a href="/entry/612194">612194</a>) inhibits GATOR1-mediated stimulation of GTP hydrolysis by RAGA, whereas weaker interactions between the NPRL2-NPRL3 heterodimer and RAGA execute GAP activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29590090" 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 genomic sequence analysis, <a href="#3" class="mim-tip-reference" title="Lerman, M. I., Minna, J. D. <strong>The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes.</strong> Cancer Res. 60: 6116-6133, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11085536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11085536</a>]" pmid="11085536">Lerman and Minna (2000)</a> determined that the NPRL2 gene resides in a 120-kb critical region for a lung cancer tumor suppressor gene on chromosome 3p21.3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11085536" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#1" class="mim-tip-reference" title="Bar-Peled, L., Chantranupong, L., Cherniack, A. D., Chen, W. W., Ottina, K. A., Grabiner, B. C., Spear, E. D., Carter, S. L., Meyerson, M., Sabatini, D. M. <strong>A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1.</strong> Science 340: 1100-1106, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23723238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23723238</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23723238[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.1232044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23723238">Bar-Peled et al. (2013)</a> identified the octameric GATOR (GTPase-activating protein (GAP) activity toward RAGs) complex as a critical regulator of the pathway that signals amino acid sufficiency to mTORC1 (see <a href="/entry/601231">601231</a>). GATOR is composed of 2 subcomplexes, GATOR1 and GATOR2. Inhibition of the GATOR1 subunits DEPDC5 (<a href="/entry/614191">614191</a>), NPRL2, and NPRL3 (<a href="/entry/600928">600928</a>) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of the GATOR2 subunits MIOS (<a href="/entry/615359">615359</a>), WDR24 (<a href="/entry/620307">620307</a>), WDR59 (<a href="/entry/617418">617418</a>), SEH1L (<a href="/entry/609263">609263</a>), and SEC13 (<a href="/entry/600152">600152</a>) suppresses mTORC1 signaling, and epistasis analysis shows that GATOR2 negatively regulates DEPDC5. GATOR1 has GAP activity for RAGA and RAGB (<a href="/entry/300725">300725</a>), and its components are mutated in human cancer. In cancer cells with inactivating mutations in GATOR1, mTORC1 is hyperactive and insensitive to amino acid starvation, and such cells are hypersensitive to rapamycin, an mTORC1 inhibitor. Thus, <a href="#1" class="mim-tip-reference" title="Bar-Peled, L., Chantranupong, L., Cherniack, A. D., Chen, W. W., Ottina, K. A., Grabiner, B. C., Spear, E. D., Carter, S. L., Meyerson, M., Sabatini, D. M. <strong>A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1.</strong> Science 340: 1100-1106, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23723238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23723238</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23723238[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.1232044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23723238">Bar-Peled et al. (2013)</a> concluded that they had identified a key negative regulator of the RAG GTPases and revealed that, like other mTORC1 regulators, RAG function can be deregulated in cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23723238" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using HEK293 cells, <a href="#2" class="mim-tip-reference" title="Gu, X., Orozco, J. M., Saxton, R. A., Condon, K. J., Liu, G. Y., Krawczyk, P. A., Scaria, S. M., Harper, J. W., Gygi, S. P., Sabatini, D. M. <strong>SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway.</strong> Science 358: 813-818, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29123071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29123071</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29123071[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.aao3265" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29123071">Gu et al. (2017)</a> found that SAMTOR (BMT2; <a href="/entry/617855">617855</a>) bound the GATOR1-KICSTOR (see <a href="/entry/617420">617420</a>) supercomplex, and that SAMTOR-GATOR1-KICSTOR inhibited MTORC1 signaling at lysosomes. Binding of S-adenosylmethionine (SAM) to SAMTOR interfered with binding of SAMTOR to GATOR1-KICSTOR and permitted MTORC1 signaling. Methionine starvation reduced SAM levels, promoting association of SAMTOR with GATOR1-KICSTOR and inhibition of MTORC1 lysosomal signaling. The authors concluded that SAMTOR senses methionine availability via SAM binding and thereby links methionine availability with MTORC1 signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29123071" 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 10 patients from 5 unrelated families with focal epilepsy with variable foci-2 (FFEVF2; <a href="/entry/617116">617116</a>), <a href="#4" class="mim-tip-reference" title="Ricos, M. G., Hodgson, B. L., Pippucci, T., Saidin, A., Ong, Y. S., Heron, S. E., Licchetta, L., Bisulli, F., Bayly, M. A., Hughes, J., Baldassari, S., Palombo, F., and 11 others. <strong>Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy.</strong> Ann. Neurol. 79: 120-131, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26505888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26505888</a>] [<a href="https://doi.org/10.1002/ana.24547" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26505888">Ricos et al. (2016)</a> identified 5 different heterozygous mutations in the NPRL2 gene (see, e.g., <a href="#0001">607072.0001</a>-<a href="#0003">607072.0003</a>), including 2 truncating mutations and 3 missense mutations. There was evidence of incomplete penetrance. The mutation in 1 large family was found by exome sequencing; the remaining probands were ascertained from a cohort of 404 individuals with focal epilepsy who underwent targeted sequencing for genes in the GATOR1 complex. Functional studies of the variants and studies of patient cells were not performed. The findings suggested that loss of function of the GATOR1 complex due to NPRL2 mutations can cause deregulated cellular growth and may play an important role in cortical dysplasia and focal epilepsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26505888" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 French sisters with FFEVF2, <a href="#6" class="mim-tip-reference" title="Weckhuysen, S., Marsan, E., Lambrecq, V., Marchal, C., Morin-Brureau, M., An-Gourfinkel, I., Baulac, M., Fohlen, M., Zetchi, C. K., Seeck, M., de la Grange, P., Dermaut, B., Meurs, A., Thomas, P., Chassoux, F., Leguern, E., Picard, F., Baulac, S. <strong>Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia.</strong> Epilepsia 57: 994-1003, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27173016/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27173016</a>] [<a href="https://doi.org/10.1111/epi.13391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27173016">Weckhuysen et al. (2016)</a> identified a heterozygous frameshift mutation in the NPRL2 gene (<a href="#0004">607072.0004</a>). The mutation, which was found by sequencing a targeted epilepsy gene panel, was confirmed by Sanger sequencing. The unaffected father and an unaffected sib also carried the mutation, consistent with incomplete penetrance. Brain sample from 1 of the patients, who had focal cortical dysplasia, showed hyperactivation of the mTOR pathway in neurons of normal appearance. These findings suggested that the NPRL2 mutation resulted in a loss of function of the GATOR1 complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27173016" 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 daughter (family 1) with familial focal epilepsy with variable foci-2 (FFEVF2; <a href="/entry/617116">617116</a>), <a href="#4" class="mim-tip-reference" title="Ricos, M. G., Hodgson, B. L., Pippucci, T., Saidin, A., Ong, Y. S., Heron, S. E., Licchetta, L., Bisulli, F., Bayly, M. A., Hughes, J., Baldassari, S., Palombo, F., and 11 others. <strong>Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy.</strong> Ann. Neurol. 79: 120-131, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26505888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26505888</a>] [<a href="https://doi.org/10.1002/ana.24547" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26505888">Ricos et al. (2016)</a> identified a heterozygous c.100C-T transition (c.100C-T, NM_006545.4) in the NPRL2 gene, resulting in an arg34-to-ter (R34X) substitution. The mutation was not found in the dbSNP, Exome Variant Server, or ExAC databases. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26505888" 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> rs886037964 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886037964;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/rs886037964?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=rs886037964" 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=rs886037964" 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 woman (family 2) with familial focal epilepsy with variable foci-2 (FFEVF2; <a href="/entry/617116">617116</a>), <a href="#4" class="mim-tip-reference" title="Ricos, M. G., Hodgson, B. L., Pippucci, T., Saidin, A., Ong, Y. S., Heron, S. E., Licchetta, L., Bisulli, F., Bayly, M. A., Hughes, J., Baldassari, S., Palombo, F., and 11 others. <strong>Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy.</strong> Ann. Neurol. 79: 120-131, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26505888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26505888</a>] [<a href="https://doi.org/10.1002/ana.24547" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26505888">Ricos et al. (2016)</a> identified a heterozygous c.883C-T transition (c.883C-T, NM_006545.4) in the NPRL2 gene, resulting in an arg295-to-ter (R295X) substitution. The patient's unaffected daughter also carried the mutation, consistent with incomplete penetrance. The mutation was not found in the dbSNP, Exome Variant Server, or ExAC databases. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26505888" 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 5 members of a 3-generation family (family 5) with familial focal epilepsy with variable foci-2 (FFEVF2; <a href="/entry/617116">617116</a>), <a href="#4" class="mim-tip-reference" title="Ricos, M. G., Hodgson, B. L., Pippucci, T., Saidin, A., Ong, Y. S., Heron, S. E., Licchetta, L., Bisulli, F., Bayly, M. A., Hughes, J., Baldassari, S., Palombo, F., and 11 others. <strong>Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy.</strong> Ann. Neurol. 79: 120-131, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26505888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26505888</a>] [<a href="https://doi.org/10.1002/ana.24547" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26505888">Ricos et al. (2016)</a> identified a heterozygous c.314T-C transition (c.314T-C, NM_006545.4) in the NPRL2 gene, resulting in an leu105-to-pro (L105P) substitution. One unaffected family member carried the mutation, consistent with incomplete penetrance. The mutation, which was found by exome sequencing, was not found in the dbSNP, Exome Variant Server, or ExAC databases. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26505888" 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">rs886037966 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886037966;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=rs886037966" 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=rs886037966" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 French sisters (family E) with familial focal epilepsy with variable foci-2 (FFEVF2; <a href="/entry/617116">617116</a>), <a href="#6" class="mim-tip-reference" title="Weckhuysen, S., Marsan, E., Lambrecq, V., Marchal, C., Morin-Brureau, M., An-Gourfinkel, I., Baulac, M., Fohlen, M., Zetchi, C. K., Seeck, M., de la Grange, P., Dermaut, B., Meurs, A., Thomas, P., Chassoux, F., Leguern, E., Picard, F., Baulac, S. <strong>Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia.</strong> Epilepsia 57: 994-1003, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27173016/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27173016</a>] [<a href="https://doi.org/10.1111/epi.13391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27173016">Weckhuysen et al. (2016)</a> identified a heterozygous 2-bp deletion (c.68_69delCT, NM_006545) in exon 1 of the NPRL2 gene, resulting in a frameshift and premature termination (Ile23AspfsTer6). The mutation, which was found by sequencing a targeted epilepsy gene panel, was confirmed by Sanger sequencing and filtered against the Exome Variant Server database; it was not found in the ExAC database. The unaffected father and an unaffected sib also carried the mutation, consistent with incomplete penetrance. A distant relative on the paternal side of the family with an unspecified epilepsy also carried the mutation. Analysis of patient cells showed that the mutant transcript was not subject to nonsense-mediated mRNA decay, but was predicted to result in a very truncated protein. Brain sample from 1 of the patients, who had focal cortical dysplasia, showed hyperactivation of the mTOR pathway in neurons of normal appearance. These findings suggested that the NPRL2 mutation resulted in a loss of function of the GATOR1 complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27173016" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<span class="mim-font">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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</h4>
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<a id="1" class="mim-anchor"></a>
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<a id="Bar-Peled2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Bar-Peled, L., Chantranupong, L., Cherniack, A. D., Chen, W. W., Ottina, K. A., Grabiner, B. C., Spear, E. D., Carter, S. L., Meyerson, M., Sabatini, D. M.
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<strong>A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1.</strong>
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Science 340: 1100-1106, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23723238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23723238</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23723238[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23723238" 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.1232044" target="_blank">Full Text</a>]
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<a id="Gu2017" class="mim-anchor"></a>
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<div class="">
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Gu, X., Orozco, J. M., Saxton, R. A., Condon, K. J., Liu, G. Y., Krawczyk, P. A., Scaria, S. M., Harper, J. W., Gygi, S. P., Sabatini, D. M.
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<strong>SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway.</strong>
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Science 358: 813-818, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29123071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29123071</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29123071[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29123071" 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.aao3265" target="_blank">Full Text</a>]
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<a id="3" class="mim-anchor"></a>
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<a id="Lerman2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Lerman, M. I., Minna, J. D.
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<strong>The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes.</strong>
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Cancer Res. 60: 6116-6133, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11085536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11085536</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11085536" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="4" class="mim-anchor"></a>
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<a id="Ricos2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ricos, M. G., Hodgson, B. L., Pippucci, T., Saidin, A., Ong, Y. S., Heron, S. E., Licchetta, L., Bisulli, F., Bayly, M. A., Hughes, J., Baldassari, S., Palombo, F., and 11 others.
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<strong>Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy.</strong>
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Ann. Neurol. 79: 120-131, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26505888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26505888</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26505888" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.24547" target="_blank">Full Text</a>]
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<a id="5" class="mim-anchor"></a>
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<a id="Shen2018" class="mim-anchor"></a>
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<p class="mim-text-font">
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Shen, K., Huang, R. K., Brignole, E. J., Condon, K. J., Valenstein, M. L., Chantranupong, L., Bomaliyamu, A., Choe, A., Hong, C., Yu, Z., Sabatini, D. M.
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<strong>Architecture of the human GATOR1 and GATOR1-Rag GTPases complexes.</strong>
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Nature 556: 64-69, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29590090/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29590090</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29590090[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29590090" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature26158" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="6" class="mim-anchor"></a>
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<a id="Weckhuysen2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Weckhuysen, S., Marsan, E., Lambrecq, V., Marchal, C., Morin-Brureau, M., An-Gourfinkel, I., Baulac, M., Fohlen, M., Zetchi, C. K., Seeck, M., de la Grange, P., Dermaut, B., Meurs, A., Thomas, P., Chassoux, F., Leguern, E., Picard, F., Baulac, S.
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<strong>Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia.</strong>
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Epilepsia 57: 994-1003, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27173016/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27173016</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27173016" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/epi.13391" target="_blank">Full Text</a>]
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</p>
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</div>
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</ol>
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<br />
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<a id="contributors" class="mim-anchor"></a>
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 08/27/2018
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Patricia A. Hartz - updated : 01/29/2018<br>Cassandra L. Kniffin - updated : 09/20/2016
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</div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Paul J. Converse : 6/26/2002
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</span>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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mgross : 03/30/2023
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</span>
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<div class="row collapse" id="mimCollapseEditHistory">
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<span class="mim-text-font">
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alopez : 08/27/2018<br>mgross : 01/29/2018<br>mgross : 03/30/2017<br>carol : 09/21/2016<br>ckniffin : 09/20/2016<br>mgross : 08/25/2016<br>alopez : 07/07/2014<br>alopez : 9/28/2004<br>mgross : 6/27/2002<br>mgross : 6/26/2002
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<h3>
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<span class="mim-font">
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<strong>*</strong> 607072
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<h3>
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NPR2-LIKE PROTEIN, GATOR1 COMPLEX SUBUNIT; NPRL2
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</h3>
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</div>
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<div>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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NPR2, S. CEREVISIAE, HOMOLOG OF; NPR2<br />
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NPR2L<br />
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TUMOR SUPPRESSOR CANDIDATE 4; TUSC4
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: NPRL2</em></strong>
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</span>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 3p21.31
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Genomic coordinates <span class="small">(GRCh38)</span> : 3:50,347,330-50,350,775 </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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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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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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<tbody>
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<td rowspan="1">
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<span class="mim-font">
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3p21.31
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</td>
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<td>
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<span class="mim-font">
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Epilepsy, familial focal, with variable foci 2
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</td>
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<td>
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<span class="mim-font">
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617116
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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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</span>
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</td>
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</tbody>
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<br />
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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 NPRL2 gene encodes a subunit of the GATOR1 complex, which regulates the mTORC1 (see 601231) signaling pathway. Other GATOR1 subunits include DEPDC5 (614191) and NPRL3 (600928) (summary by Ricos et al., 2016). </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 physical cloning methodologies and bioinformatic computational analyses, Lerman and Minna (2000) identified a number of genes, including NPR2L, which they called NPRL2, in a region of chromosome 3p21.3 that is associated with a putative lung cancer tumor suppressor gene. The deduced 380-amino acid conserved soluble protein, which is 97% identical to the mouse protein and orthologous to the yeast nitrogen permease gene Npr2, contains a bipartite nuclear localization signal and a granulin protein-binding domain. The authors identified multiple NPRL2 splice variants. Northern blot analysis revealed expression of a 1.5-kb transcript that was most abundant in skeletal muscle, followed by brain, liver, and pancreas, with lower amounts in lung, kidney, placenta, and heart. NPRL2 was expressed in most lung cancer cell lines tested. Mutations, including stop mutations, were found in approximately 5% of cell lines tested, but none of the genes identified in the search had a high frequency of mutations. Lerman and Minna (2000) proposed that NPRL2 is a candidate for functional tumor suppressor gene studies. </p><p>Ricos et al. (2016) found expression of the NPRL3 gene in all human brain regions analyzed, including frontal, temporal, parietal, and occipital lobes. A similar pattern of expression was found in both embryonic and adult mouse brain. All 3 genes in the GATOR1 complex showed a striking similarity in tissue distribution. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By genomic sequence analysis, Lerman and Minna (2000) determined that the NPRL2 gene contains 11 exons and spans 3.3 kb. </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>Biochemical Features</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>Cryoelectron Microscopy</em></strong></p><p>
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Shen et al. (2018) used cryoelectron microscopy to solve structures of GATOR1 and GATOR1-RAG GTPases complexes. GATOR1 adopts an extended architecture with a cavity in the middle; NPRL2 links DEPDC5 and NPRL3, and DEPDC5 contacts the RAG GTPase heterodimer. Biochemical analyses revealed that this GATOR1-RAG GTPases structure is inhibitory, and that at least 2 binding modes must exist between the RAG GTPases and GATOR1. Direct interaction of DEPDC5 with RAGA (612194) inhibits GATOR1-mediated stimulation of GTP hydrolysis by RAGA, whereas weaker interactions between the NPRL2-NPRL3 heterodimer and RAGA execute GAP activity. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>By genomic sequence analysis, Lerman and Minna (2000) determined that the NPRL2 gene resides in a 120-kb critical region for a lung cancer tumor suppressor gene on chromosome 3p21.3. </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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<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>Bar-Peled et al. (2013) identified the octameric GATOR (GTPase-activating protein (GAP) activity toward RAGs) complex as a critical regulator of the pathway that signals amino acid sufficiency to mTORC1 (see 601231). GATOR is composed of 2 subcomplexes, GATOR1 and GATOR2. Inhibition of the GATOR1 subunits DEPDC5 (614191), NPRL2, and NPRL3 (600928) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of the GATOR2 subunits MIOS (615359), WDR24 (620307), WDR59 (617418), SEH1L (609263), and SEC13 (600152) suppresses mTORC1 signaling, and epistasis analysis shows that GATOR2 negatively regulates DEPDC5. GATOR1 has GAP activity for RAGA and RAGB (300725), and its components are mutated in human cancer. In cancer cells with inactivating mutations in GATOR1, mTORC1 is hyperactive and insensitive to amino acid starvation, and such cells are hypersensitive to rapamycin, an mTORC1 inhibitor. Thus, Bar-Peled et al. (2013) concluded that they had identified a key negative regulator of the RAG GTPases and revealed that, like other mTORC1 regulators, RAG function can be deregulated in cancer. </p><p>Using HEK293 cells, Gu et al. (2017) found that SAMTOR (BMT2; 617855) bound the GATOR1-KICSTOR (see 617420) supercomplex, and that SAMTOR-GATOR1-KICSTOR inhibited MTORC1 signaling at lysosomes. Binding of S-adenosylmethionine (SAM) to SAMTOR interfered with binding of SAMTOR to GATOR1-KICSTOR and permitted MTORC1 signaling. Methionine starvation reduced SAM levels, promoting association of SAMTOR with GATOR1-KICSTOR and inhibition of MTORC1 lysosomal signaling. The authors concluded that SAMTOR senses methionine availability via SAM binding and thereby links methionine availability with MTORC1 signaling. </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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<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>In 10 patients from 5 unrelated families with focal epilepsy with variable foci-2 (FFEVF2; 617116), Ricos et al. (2016) identified 5 different heterozygous mutations in the NPRL2 gene (see, e.g., 607072.0001-607072.0003), including 2 truncating mutations and 3 missense mutations. There was evidence of incomplete penetrance. The mutation in 1 large family was found by exome sequencing; the remaining probands were ascertained from a cohort of 404 individuals with focal epilepsy who underwent targeted sequencing for genes in the GATOR1 complex. Functional studies of the variants and studies of patient cells were not performed. The findings suggested that loss of function of the GATOR1 complex due to NPRL2 mutations can cause deregulated cellular growth and may play an important role in cortical dysplasia and focal epilepsy. </p><p>In 2 French sisters with FFEVF2, Weckhuysen et al. (2016) identified a heterozygous frameshift mutation in the NPRL2 gene (607072.0004). The mutation, which was found by sequencing a targeted epilepsy gene panel, was confirmed by Sanger sequencing. The unaffected father and an unaffected sib also carried the mutation, consistent with incomplete penetrance. Brain sample from 1 of the patients, who had focal cortical dysplasia, showed hyperactivation of the mTOR pathway in neurons of normal appearance. These findings suggested that the NPRL2 mutation resulted in a loss of function of the GATOR1 complex. </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>ALLELIC VARIANTS</strong>
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</span>
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<strong>4 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 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 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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NPRL2, ARG34TER
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<br />
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SNP: rs886037963,
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ClinVar: RCV000241310, RCV001266233, RCV002274955, RCV003320623
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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 daughter (family 1) with familial focal epilepsy with variable foci-2 (FFEVF2; 617116), Ricos et al. (2016) identified a heterozygous c.100C-T transition (c.100C-T, NM_006545.4) in the NPRL2 gene, resulting in an arg34-to-ter (R34X) substitution. The mutation was not found in the dbSNP, Exome Variant Server, or ExAC databases. Functional studies of the variant and studies of patient cells were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 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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NPRL2, ARG295TER
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<br />
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SNP: rs886037964,
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gnomAD: rs886037964,
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ClinVar: RCV000241491, RCV003325477
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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 woman (family 2) with familial focal epilepsy with variable foci-2 (FFEVF2; 617116), Ricos et al. (2016) identified a heterozygous c.883C-T transition (c.883C-T, NM_006545.4) in the NPRL2 gene, resulting in an arg295-to-ter (R295X) substitution. The patient's unaffected daughter also carried the mutation, consistent with incomplete penetrance. The mutation was not found in the dbSNP, Exome Variant Server, or ExAC databases. Functional studies of the variant and studies of patient cells were not performed. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0003 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 2</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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NPRL2, LEU105PRO
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<br />
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SNP: rs886037965,
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ClinVar: RCV000241152
|
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 members of a 3-generation family (family 5) with familial focal epilepsy with variable foci-2 (FFEVF2; 617116), Ricos et al. (2016) identified a heterozygous c.314T-C transition (c.314T-C, NM_006545.4) in the NPRL2 gene, resulting in an leu105-to-pro (L105P) substitution. One unaffected family member carried the mutation, consistent with incomplete penetrance. The mutation, which was found by exome sequencing, was not found in the dbSNP, Exome Variant Server, or ExAC databases. Functional studies of the variant and studies of patient cells were not performed. </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>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
NPRL2, 2-BP DEL, 68CT
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|
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|
|
|
<br />
|
|
|
|
SNP: rs886037966,
|
|
|
|
|
|
|
|
ClinVar: RCV000241360
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 French sisters (family E) with familial focal epilepsy with variable foci-2 (FFEVF2; 617116), Weckhuysen et al. (2016) identified a heterozygous 2-bp deletion (c.68_69delCT, NM_006545) in exon 1 of the NPRL2 gene, resulting in a frameshift and premature termination (Ile23AspfsTer6). The mutation, which was found by sequencing a targeted epilepsy gene panel, was confirmed by Sanger sequencing and filtered against the Exome Variant Server database; it was not found in the ExAC database. The unaffected father and an unaffected sib also carried the mutation, consistent with incomplete penetrance. A distant relative on the paternal side of the family with an unspecified epilepsy also carried the mutation. Analysis of patient cells showed that the mutant transcript was not subject to nonsense-mediated mRNA decay, but was predicted to result in a very truncated protein. Brain sample from 1 of the patients, who had focal cortical dysplasia, showed hyperactivation of the mTOR pathway in neurons of normal appearance. These findings suggested that the NPRL2 mutation resulted in a loss of function of the GATOR1 complex. </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>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
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<p />
|
|
</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
|
|
Bar-Peled, L., Chantranupong, L., Cherniack, A. D., Chen, W. W., Ottina, K. A., Grabiner, B. C., Spear, E. D., Carter, S. L., Meyerson, M., Sabatini, D. M.
|
|
<strong>A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1.</strong>
|
|
Science 340: 1100-1106, 2013.
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[PubMed: 23723238]
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[Full Text: https://doi.org/10.1126/science.1232044]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Gu, X., Orozco, J. M., Saxton, R. A., Condon, K. J., Liu, G. Y., Krawczyk, P. A., Scaria, S. M., Harper, J. W., Gygi, S. P., Sabatini, D. M.
|
|
<strong>SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway.</strong>
|
|
Science 358: 813-818, 2017.
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[PubMed: 29123071]
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[Full Text: https://doi.org/10.1126/science.aao3265]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Lerman, M. I., Minna, J. D.
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<strong>The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes.</strong>
|
|
Cancer Res. 60: 6116-6133, 2000.
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[PubMed: 11085536]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Ricos, M. G., Hodgson, B. L., Pippucci, T., Saidin, A., Ong, Y. S., Heron, S. E., Licchetta, L., Bisulli, F., Bayly, M. A., Hughes, J., Baldassari, S., Palombo, F., and 11 others.
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|
<strong>Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy.</strong>
|
|
Ann. Neurol. 79: 120-131, 2016.
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[PubMed: 26505888]
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[Full Text: https://doi.org/10.1002/ana.24547]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Shen, K., Huang, R. K., Brignole, E. J., Condon, K. J., Valenstein, M. L., Chantranupong, L., Bomaliyamu, A., Choe, A., Hong, C., Yu, Z., Sabatini, D. M.
|
|
<strong>Architecture of the human GATOR1 and GATOR1-Rag GTPases complexes.</strong>
|
|
Nature 556: 64-69, 2018.
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[PubMed: 29590090]
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[Full Text: https://doi.org/10.1038/nature26158]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Weckhuysen, S., Marsan, E., Lambrecq, V., Marchal, C., Morin-Brureau, M., An-Gourfinkel, I., Baulac, M., Fohlen, M., Zetchi, C. K., Seeck, M., de la Grange, P., Dermaut, B., Meurs, A., Thomas, P., Chassoux, F., Leguern, E., Picard, F., Baulac, S.
|
|
<strong>Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia.</strong>
|
|
Epilepsia 57: 994-1003, 2016.
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|
[PubMed: 27173016]
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[Full Text: https://doi.org/10.1111/epi.13391]
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</p>
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</li>
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</ol>
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<div>
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<br />
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</div>
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 08/27/2018<br>Patricia A. Hartz - updated : 01/29/2018<br>Cassandra L. Kniffin - updated : 09/20/2016
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</span>
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</div>
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Paul J. Converse : 6/26/2002
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<span class="text-nowrap mim-text-font">
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Edit History:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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mgross : 03/30/2023<br>alopez : 08/27/2018<br>mgross : 01/29/2018<br>mgross : 03/30/2017<br>carol : 09/21/2016<br>ckniffin : 09/20/2016<br>mgross : 08/25/2016<br>alopez : 07/07/2014<br>alopez : 9/28/2004<br>mgross : 6/27/2002<br>mgross : 6/26/2002
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NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers,
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and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal
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medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
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OMIM<sup>®</sup> and Online Mendelian Inheritance in Man<sup>®</sup> are registered trademarks of the Johns Hopkins University.
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Thank you in advance for your generous support, <br />
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Ada Hamosh, MD, MPH <br />
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Scientific Director, OMIM <br />
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