3364 lines
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Entry
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- *600928 - NITROGEN PERMEASE REGULATOR-LIKE 3; NPRL3
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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">*600928</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/600928">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000103148;t=ENST00000611875" 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=8131" 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=600928" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000103148;t=ENST00000611875" 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_001039476,NM_001077350,NM_001243247,NM_001243248,NM_001243249" 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_001077350" 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=600928" 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=11866&isoform_id=11866_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/NPRL3" 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/984125,1817580,13278840,15215468,18202492,66350792,66350793,66350800,66350801,87116675,90653006,116292162,119606271,119606273,119606274,122891455,193786896,221039886,221042390,221043318,342837743,342837745,342837747,2528844953" 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/Q12980" 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=8131" 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=ENSG00000103148;t=ENST00000611875" 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=NPRL3" 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=NPRL3" 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+8131" 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/NPRL3" 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:8131" 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/8131" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr16&hgg_gene=ENST00000611875.5&hgg_start=85386&hgg_end=138673&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:14124" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:14124" 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/nprl3" 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=600928[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=600928[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/NPRL3/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000103148" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=NPRL3" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=NPRL3" 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=NPRL3" 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=NPRL3&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/PA25550" 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:14124" 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/FBgn0036397.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:109258" 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/NPRL3#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:109258" 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/8131/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=8131" 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=WBGene00018072;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-030131-1348" 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:8131" 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=NPRL3&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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600928
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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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NITROGEN PERMEASE REGULATOR-LIKE 3; NPRL3
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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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CHROMOSOME 16 OPEN READING FRAME 35; C16ORF35<br />
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CONSERVED GENE TELOMERIC TO ALPHA GLOBIN CLUSTER
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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=NPRL3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">NPRL3</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/16/14?start=-3&limit=10&highlight=14">16p13.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr16:85386-138673&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">16:85,386-138,673</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">
|
|
<a href="/geneMap/16/14?start=-3&limit=10&highlight=14">
|
|
16p13.3
|
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</a>
|
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</span>
|
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</td>
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|
|
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<td>
|
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<span class="mim-font">
|
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Epilepsy, familial focal, with variable foci 3
|
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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/617118"> 617118 </a>
|
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|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
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<abbr class="mim-tip-hint" title="Autosomal 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>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/600928" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/600928" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
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</div>
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<p>The NPRL3 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 NPRL2 (<a href="/entry/607072">607072</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><a href="#7" class="mim-tip-reference" title="Vyas, P., Vickers, M. A., Picketts, D. J., Higgs, D. R. <strong>Conservation of position and sequence of a novel, widely expressed gene containing the major human alpha-globin regulatory element.</strong> Genomics 29: 679-689, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8575760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8575760</a>] [<a href="https://doi.org/10.1006/geno.1995.9951" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8575760">Vyas et al. (1995)</a> reported the characterization of a gene (designated '-14' by them to indicate its relative position) that lies adjacent to the alpha globin gene cluster on chromosome 16p13.3. The -14 cDNA encodes a predicted 544- or 569-amino acid protein, depending on the alternative splicing of exon 5. Two mRNAs of 3.2 and 2.5 kb were detected in a variety of cell lines (<a href="#8" class="mim-tip-reference" title="Vyas, P., Vickers, M. A., Simmons, D. L., Ayyub, H., Craddock, C. F., Higgs, D. R. <strong>Cis-acting sequences regulating expression of the human alpha-globin cluster lie within constitutively open chromatin.</strong> Cell 69: 781-793, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1591777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1591777</a>] [<a href="https://doi.org/10.1016/0092-8674(92)90290-s" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1591777">Vyas et al., 1992</a>). Curiously, a previously identified erythroid-specific regulatory element occurs within intron 5. This regulatory sequence does not influence expression of the gene, which has a GC-rich promoter (unlike the TATA-type promoters of the alpha globin loci). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8575760+1591777" 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><a href="#7" class="mim-tip-reference" title="Vyas, P., Vickers, M. A., Picketts, D. J., Higgs, D. R. <strong>Conservation of position and sequence of a novel, widely expressed gene containing the major human alpha-globin regulatory element.</strong> Genomics 29: 679-689, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8575760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8575760</a>] [<a href="https://doi.org/10.1006/geno.1995.9951" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8575760">Vyas et al. (1995)</a> determined that the -14 gene contains 15 exons and spans about 55 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8575760" 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><a href="#7" class="mim-tip-reference" title="Vyas, P., Vickers, M. A., Picketts, D. J., Higgs, D. R. <strong>Conservation of position and sequence of a novel, widely expressed gene containing the major human alpha-globin regulatory element.</strong> Genomics 29: 679-689, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8575760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8575760</a>] [<a href="https://doi.org/10.1006/geno.1995.9951" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8575760">Vyas et al. (1995)</a> identified the -14 gene adjacent to the alpha globin gene cluster on chromosome 16p13.3. The authors showed that the sequence of the gene and its location adjacent to alpha globin loci has been conserved for at least 270 million years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8575760" 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 (<a href="/entry/607072">607072</a>), and NPRL3 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 (<a href="/entry/612194">612194</a>) 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-3 (FFEVF3; <a href="/entry/617118">617118</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 NPRL3 gene (see, e.g., <a href="#0001">600928.0001</a>-<a href="#0002">600928.0002</a>), including 3 truncating mutations and 2 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 4 members of a family with FFEVF3, <a href="#6" class="mim-tip-reference" title="Sim, J. C., Scerri, T., Fanjul-Fernandez, M., Riseley, J. R., Gillies, G., Pope, K., van Roozendaal, H., Heng, J. I., Mandelstam, S. A., McGilivray, G., MacGregor, D., Kannan, L., Maixner, W., Harvey, A. S., Amor, D. J., Delatycki, M. B., Crino, P. B., Bahlo, M., Lockhart, P. J., Leventer, R. J. <strong>Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3.</strong> Ann. Neurol. 79: 132-137, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26285051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26285051</a>] [<a href="https://doi.org/10.1002/ana.24502" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26285051">Sim et al. (2016)</a> identified a heterozygous frameshift mutation in the NPRL3 gene (<a href="#0002">600928.0002</a>). The mutation, which was found by whole-exome sequencing, showed incomplete penetrance in the family. Two of the patients had focal cortical dysplasia (FCD). Sequence analysis of the NPRL3 gene in 52 individuals with FCD identified 2 unrelated patients with heterozygous mutations (see, e.g., <a href="#0003">600928.0003</a>). Resected dysplastic brain tissue from 3 patients with truncating mutations showed a 50% decrease in NPRL3, consistent with haploinsufficiency, as well as evidence of activation of the mTOR pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26285051" 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 affected members of 2 unrelated families with FFEVF3 and FCD, <a href="#9" 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 2 different heterozygous truncating mutations in the NPRL3 gene (<a href="#0004">600928.0004</a>-<a href="#0005">600928.0005</a>). The mutations, which were found by sequencing a targeted epilepsy gene panel in 93 probands with focal epilepsy with or without FCD, were confirmed by Sanger sequencing. <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><p>In 133 members of an Old Order Mennonite pedigree with FFEVF3, <a href="#3" class="mim-tip-reference" title="Iffland, P. H., Everett, M. E., Cobb-Pitstick, K. M., Bowser, L. E., Barnes, A. E., Babus, J. K., Romanowski, A. J., Baybis, M., Elziny, S., Puffenberger, E. G., Gonzaga-Jauregui, C., Poulopoulos, A., Carson, V. J., Crino, P. B. <strong>NPRL3 loss alters neuronal morphology, mTOR localization, cortical lamination and seizure threshold.</strong> Brain 145: 3872-3885, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35136953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35136953</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35136953[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/10.1093/brain/awac044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35136953">Iffland et al. (2022)</a> identified a heterozygous mutation in the NPRL3 gene (c.349delG; <a href="#0006">600928.0006</a>). Pedigree analysis demonstrated that all of the mutation carriers traced back to a single founder. Of the 133 patients, 48 had a history of seizures and 85 had no history of seizures. Whole-exome sequencing comparing 37 patients with no seizures to 24 patients with seizures did not identify any potential modifier genes that explained the epilepsy penetrance. <a href="#3" class="mim-tip-reference" title="Iffland, P. H., Everett, M. E., Cobb-Pitstick, K. M., Bowser, L. E., Barnes, A. E., Babus, J. K., Romanowski, A. J., Baybis, M., Elziny, S., Puffenberger, E. G., Gonzaga-Jauregui, C., Poulopoulos, A., Carson, V. J., Crino, P. B. <strong>NPRL3 loss alters neuronal morphology, mTOR localization, cortical lamination and seizure threshold.</strong> Brain 145: 3872-3885, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35136953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35136953</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35136953[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/10.1093/brain/awac044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35136953">Iffland et al. (2022)</a> analyzed Nprl3 knockout N2a cells and showed that the cells had enhanced ribosomal S6 protein (PS6) phosphorylation compared to wildtype cells. This enhanced PS6 phosphorylation was corrected with treatment with rapamycin. However, PS6 phosphorylation was not corrected in the Nprl3 knockout cells under conditions of amino acid starvation, indicating that Nprl3 abrogates the effect of GATOR1 on mTOR activation. The Nprl3 knockout N2a cells formed abnormal cellular aggregates, which was corrected with rapamycin treatment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35136953" 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 3 members of a family (family 6) with familial focal epilepsy with variable foci-3 (FFEVF3; <a href="/entry/617118">617118</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 1-bp insertion (c.835_836insT, NM_001077350.2) in the NPRL3 gene, resulting in a frameshift and premature termination (Ser279PhefsTer52). The mutation, which was found by whole-exome sequencing, was not found in the dbSNP, Exome Variant Server, or ExAC databases. The mutation was also confirmed by linkage analysis in this family. Two unaffected individuals carried the mutation, consistent with incomplete penetrance. Another family member with febrile seizures also carried the mutation. <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 a father and his 2 sons (family 7) with familial focal epilepsy with variable foci-3 (FFEVF3; <a href="/entry/617118">617118</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 2-bp insertion (c.1376_1377insAC, NM_001077350.2) in the NPRL3 gene, resulting in a frameshift and premature termination (Ser460ProfsTer20). 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><p><a href="#6" class="mim-tip-reference" title="Sim, J. C., Scerri, T., Fanjul-Fernandez, M., Riseley, J. R., Gillies, G., Pope, K., van Roozendaal, H., Heng, J. I., Mandelstam, S. A., McGilivray, G., MacGregor, D., Kannan, L., Maixner, W., Harvey, A. S., Amor, D. J., Delatycki, M. B., Crino, P. B., Bahlo, M., Lockhart, P. J., Leventer, R. J. <strong>Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3.</strong> Ann. Neurol. 79: 132-137, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26285051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26285051</a>] [<a href="https://doi.org/10.1002/ana.24502" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26285051">Sim et al. (2016)</a> identified heterozygosity for the same mutation, which they reported as c.1375_1376dupAC, resulting in a frameshift (Ser460ProfsTer20), in 4 members of a family with FFEVF3; 2 patients had focal cortical dysplasia. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing and by linkage analysis. The mutation was also found in 4 unaffected family members in previous generations, consistent with incomplete penetrance. Resected dysplastic brain tissue of 2 patients showed a 50% decrease in NPRL3, consistent with nonsense-mediated mRNA decay of the mutant transcript and haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26285051" 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">rs886037959 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886037959;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=rs886037959" 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=rs886037959" 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 6-year-old boy (patient 5) with familial focal epilepsy with variable foci-3 (FFEVF3; <a href="/entry/617118">617118</a>), <a href="#6" class="mim-tip-reference" title="Sim, J. C., Scerri, T., Fanjul-Fernandez, M., Riseley, J. R., Gillies, G., Pope, K., van Roozendaal, H., Heng, J. I., Mandelstam, S. A., McGilivray, G., MacGregor, D., Kannan, L., Maixner, W., Harvey, A. S., Amor, D. J., Delatycki, M. B., Crino, P. B., Bahlo, M., Lockhart, P. J., Leventer, R. J. <strong>Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3.</strong> Ann. Neurol. 79: 132-137, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26285051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26285051</a>] [<a href="https://doi.org/10.1002/ana.24502" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26285051">Sim et al. (2016)</a> identified a heterozygous del/ins mutation affecting the splice acceptor site of exon 13 of the NPRL3 gene (c.1352-4delACAGinsTGACCCATCC). The mutation was inherited from his asymptomatic mother. The patient was from a cohort of 52 individuals with focal cortical dysplasia who underwent sequence analysis of the NPRL3 gene. Resected dysplastic brain tissue from the patient showed a 50% decrease in NPRL3, consistent with nonsense-mediated mRNA decay of the mutant transcript and haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26285051" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 3</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs886037961 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886037961;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/rs886037961?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=rs886037961" 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=rs886037961" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a French family (family F) with familial focal epilepsy with variable foci-3 (FFEVF3; <a href="/entry/617118">617118</a>), <a href="#9" 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 c.1270C-T transition (c.1270C-T, NM_001077350) in the NPRL3 gene, resulting in an arg424-to-ter (R424X) substitution. 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. At least 1 unaffected family member carried the mutation, consistent with incomplete penetrance. Analysis of patient cells showed that the mutant transcript was subject to nonsense-mediated mRNA decay, consistent with haploinsufficiency. Brain sample from 1 of the patients, who had focal cortical dysplasia, showed hyperactivation of the mTOR pathway in normal and dysmorphic neurons. These findings suggested that the NPRL3 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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<strong>.0005 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 3</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs886037962 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886037962;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=rs886037962" 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=rs886037962" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000241093" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000241093" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000241093</a>
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<p>In 4 members of a 3-generation Swiss family (family G) with familial focal epilepsy with variable foci-3 (FFEVF3; <a href="/entry/617118">617118</a>), <a href="#9" 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 1-bp deletion (c.1070delC, NM_001077350) in the NPRL3 gene, resulting in a frameshift and premature termination (Pro357HisfsTer56). 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. <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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<strong>.0006 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 3</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1900088045 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1900088045;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=rs1900088045" 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=rs1900088045" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001067555 OR RCV003159179" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001067555, RCV003159179" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001067555...</a>
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<p>In 133 members of an Old Order Mennonite pedigree with familial focal epilepsy with variable foci-3 (FFEVF3; <a href="/entry/617118">617118</a>), <a href="#3" class="mim-tip-reference" title="Iffland, P. H., Everett, M. E., Cobb-Pitstick, K. M., Bowser, L. E., Barnes, A. E., Babus, J. K., Romanowski, A. J., Baybis, M., Elziny, S., Puffenberger, E. G., Gonzaga-Jauregui, C., Poulopoulos, A., Carson, V. J., Crino, P. B. <strong>NPRL3 loss alters neuronal morphology, mTOR localization, cortical lamination and seizure threshold.</strong> Brain 145: 3872-3885, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35136953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35136953</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35136953[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/10.1093/brain/awac044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35136953">Iffland et al. (2022)</a> identified heterozygosity for a 1-bp deletion (c.349delG) in the NPRL3 gene, predicted to result in a frameshift and premature termination (Glu117LysfsTer). The mutation was identified in each patient by whole-exome sequencing, targeted NPRL3 variant testing, or an extended carrier test targeted for the Older Order Amish and Mennonite communities. Pedigree analysis demonstrated that all of the mutation carriers traced back to a single founder. Of the 133 patients, 48 had a history of seizures and 85 had no history of seizures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35136953" 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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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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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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Iffland, P. H., Everett, M. E., Cobb-Pitstick, K. M., Bowser, L. E., Barnes, A. E., Babus, J. K., Romanowski, A. J., Baybis, M., Elziny, S., Puffenberger, E. G., Gonzaga-Jauregui, C., Poulopoulos, A., Carson, V. J., Crino, P. B.
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<strong>NPRL3 loss alters neuronal morphology, mTOR localization, cortical lamination and seizure threshold.</strong>
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Brain 145: 3872-3885, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35136953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35136953</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35136953[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=35136953" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/awac044" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="4" class="mim-anchor"></a>
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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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</p>
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</div>
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<li>
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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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<div class="">
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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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<a id="6" class="mim-anchor"></a>
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<a id="Sim2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sim, J. C., Scerri, T., Fanjul-Fernandez, M., Riseley, J. R., Gillies, G., Pope, K., van Roozendaal, H., Heng, J. I., Mandelstam, S. A., McGilivray, G., MacGregor, D., Kannan, L., Maixner, W., Harvey, A. S., Amor, D. J., Delatycki, M. B., Crino, P. B., Bahlo, M., Lockhart, P. J., Leventer, R. J.
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<strong>Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3.</strong>
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Ann. Neurol. 79: 132-137, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26285051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26285051</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26285051" 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.24502" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="7" class="mim-anchor"></a>
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<a id="Vyas1995" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vyas, P., Vickers, M. A., Picketts, D. J., Higgs, D. R.
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<strong>Conservation of position and sequence of a novel, widely expressed gene containing the major human alpha-globin regulatory element.</strong>
|
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Genomics 29: 679-689, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8575760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8575760</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8575760" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.1995.9951" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="8" class="mim-anchor"></a>
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<a id="Vyas1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vyas, P., Vickers, M. A., Simmons, D. L., Ayyub, H., Craddock, C. F., Higgs, D. R.
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<strong>Cis-acting sequences regulating expression of the human alpha-globin cluster lie within constitutively open chromatin.</strong>
|
|
Cell 69: 781-793, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1591777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1591777</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1591777" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0092-8674(92)90290-s" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="9" 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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<div>
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<br />
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</div>
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<a id="contributors" class="mim-anchor"></a>
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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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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Hilary J. Vernon - updated : 03/01/2023
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</span>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 08/27/2018<br>Patricia A. Hartz - updated : 01/29/2018<br>Cassandra L. Kniffin - updated : 09/20/2016<br>Ada Hamosh - updated : 07/07/2014
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</span>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Alan F. Scott : 11/7/1995
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</span>
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</div>
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</div>
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</div>
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<a id="editHistory" class="mim-anchor"></a>
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 09/20/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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mgross : 03/30/2023<br>carol : 03/02/2023<br>carol : 03/01/2023<br>alopez : 08/27/2018<br>mgross : 01/29/2018<br>mgross : 03/30/2017<br>carol : 09/22/2016<br>carol : 09/21/2016<br>carol : 09/21/2016<br>ckniffin : 09/20/2016<br>alopez : 07/07/2014<br>carol : 3/24/2014<br>alopez : 4/7/2009<br>joanna : 5/8/1998<br>terry : 11/13/1995<br>mark : 11/7/1995
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</span>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 600928
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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NITROGEN PERMEASE REGULATOR-LIKE 3; NPRL3
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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<div>
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<h4>
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<span class="mim-font">
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CHROMOSOME 16 OPEN READING FRAME 35; C16ORF35<br />
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CONSERVED GENE TELOMERIC TO ALPHA GLOBIN CLUSTER
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</span>
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</h4>
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</div>
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<div>
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<br />
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: NPRL3</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 16p13.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 16:85,386-138,673 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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16p13.3
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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 3
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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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617118
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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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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The NPRL3 gene encodes a subunit of the GATOR1 complex, which regulates the mTORC1 (see 601231) signaling pathway. Other GATOR1 subunits include DEPDC5 (614191) and NPRL2 (607072) (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>Vyas et al. (1995) reported the characterization of a gene (designated '-14' by them to indicate its relative position) that lies adjacent to the alpha globin gene cluster on chromosome 16p13.3. The -14 cDNA encodes a predicted 544- or 569-amino acid protein, depending on the alternative splicing of exon 5. Two mRNAs of 3.2 and 2.5 kb were detected in a variety of cell lines (Vyas et al., 1992). Curiously, a previously identified erythroid-specific regulatory element occurs within intron 5. This regulatory sequence does not influence expression of the gene, which has a GC-rich promoter (unlike the TATA-type promoters of the alpha globin loci). </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>Vyas et al. (1995) determined that the -14 gene contains 15 exons and spans about 55 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>Vyas et al. (1995) identified the -14 gene adjacent to the alpha globin gene cluster on chromosome 16p13.3. The authors showed that the sequence of the gene and its location adjacent to alpha globin loci has been conserved for at least 270 million years. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>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 (607072), and NPRL3 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 (612194) 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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<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-3 (FFEVF3; 617118), Ricos et al. (2016) identified 5 different heterozygous mutations in the NPRL3 gene (see, e.g., 600928.0001-600928.0002), including 3 truncating mutations and 2 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 4 members of a family with FFEVF3, Sim et al. (2016) identified a heterozygous frameshift mutation in the NPRL3 gene (600928.0002). The mutation, which was found by whole-exome sequencing, showed incomplete penetrance in the family. Two of the patients had focal cortical dysplasia (FCD). Sequence analysis of the NPRL3 gene in 52 individuals with FCD identified 2 unrelated patients with heterozygous mutations (see, e.g., 600928.0003). Resected dysplastic brain tissue from 3 patients with truncating mutations showed a 50% decrease in NPRL3, consistent with haploinsufficiency, as well as evidence of activation of the mTOR pathway. </p><p>In affected members of 2 unrelated families with FFEVF3 and FCD, Weckhuysen et al. (2016) identified 2 different heterozygous truncating mutations in the NPRL3 gene (600928.0004-600928.0005). The mutations, which were found by sequencing a targeted epilepsy gene panel in 93 probands with focal epilepsy with or without FCD, were confirmed by Sanger sequencing. </p><p>In 133 members of an Old Order Mennonite pedigree with FFEVF3, Iffland et al. (2022) identified a heterozygous mutation in the NPRL3 gene (c.349delG; 600928.0006). Pedigree analysis demonstrated that all of the mutation carriers traced back to a single founder. Of the 133 patients, 48 had a history of seizures and 85 had no history of seizures. Whole-exome sequencing comparing 37 patients with no seizures to 24 patients with seizures did not identify any potential modifier genes that explained the epilepsy penetrance. Iffland et al. (2022) analyzed Nprl3 knockout N2a cells and showed that the cells had enhanced ribosomal S6 protein (PS6) phosphorylation compared to wildtype cells. This enhanced PS6 phosphorylation was corrected with treatment with rapamycin. However, PS6 phosphorylation was not corrected in the Nprl3 knockout cells under conditions of amino acid starvation, indicating that Nprl3 abrogates the effect of GATOR1 on mTOR activation. The Nprl3 knockout N2a cells formed abnormal cellular aggregates, which was corrected with rapamycin treatment. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Iffland et al. (2022) used CRISPR/Cas9 to target Nprl3 in neuroglial progenitor cells in developing mouse embryos. The resulting pups had cortical laminar defects on postnatal day 3. These laminar defects were rescued with in utero treatment with rapamycin. At 5 weeks of age, the mice had abnormal EEGs and reduced seizure thresholds. Treatment with rapamycin corrected the abnormal seizure thresholds. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>6 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0001 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 3</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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NPRL3, 1-BP INS, 835T
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<br />
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SNP: rs886037958,
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ClinVar: RCV000241451
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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 3 members of a family (family 6) with familial focal epilepsy with variable foci-3 (FFEVF3; 617118), Ricos et al. (2016) identified a heterozygous 1-bp insertion (c.835_836insT, NM_001077350.2) in the NPRL3 gene, resulting in a frameshift and premature termination (Ser279PhefsTer52). The mutation, which was found by whole-exome sequencing, was not found in the dbSNP, Exome Variant Server, or ExAC databases. The mutation was also confirmed by linkage analysis in this family. Two unaffected individuals carried the mutation, consistent with incomplete penetrance. Another family member with febrile seizures also carried the mutation. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 3</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
|
NPRL3, 2-BP INS, 1376AC
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<br />
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|
|
SNP: rs886037960,
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|
|
|
|
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|
|
ClinVar: RCV000241321
|
|
|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a father and his 2 sons (family 7) with familial focal epilepsy with variable foci-3 (FFEVF3; 617118), Ricos et al. (2016) identified a heterozygous 2-bp insertion (c.1376_1377insAC, NM_001077350.2) in the NPRL3 gene, resulting in a frameshift and premature termination (Ser460ProfsTer20). 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><p>Sim et al. (2016) identified heterozygosity for the same mutation, which they reported as c.1375_1376dupAC, resulting in a frameshift (Ser460ProfsTer20), in 4 members of a family with FFEVF3; 2 patients had focal cortical dysplasia. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing and by linkage analysis. The mutation was also found in 4 unaffected family members in previous generations, consistent with incomplete penetrance. Resected dysplastic brain tissue of 2 patients showed a 50% decrease in NPRL3, consistent with nonsense-mediated mRNA decay of the mutant transcript and haploinsufficiency. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NPRL3, IVS13AS, 4-BP DEL/10-BP INS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs886037959,
|
|
|
|
|
|
|
|
ClinVar: RCV000241104
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 6-year-old boy (patient 5) with familial focal epilepsy with variable foci-3 (FFEVF3; 617118), Sim et al. (2016) identified a heterozygous del/ins mutation affecting the splice acceptor site of exon 13 of the NPRL3 gene (c.1352-4delACAGinsTGACCCATCC). The mutation was inherited from his asymptomatic mother. The patient was from a cohort of 52 individuals with focal cortical dysplasia who underwent sequence analysis of the NPRL3 gene. Resected dysplastic brain tissue from the patient showed a 50% decrease in NPRL3, consistent with nonsense-mediated mRNA decay of the mutant transcript and haploinsufficiency. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
NPRL3, ARG424TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs886037961,
|
|
|
|
|
|
gnomAD: rs886037961,
|
|
|
|
|
|
ClinVar: RCV000241508, RCV002281079
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a French family (family F) with familial focal epilepsy with variable foci-3 (FFEVF3; 617118), Weckhuysen et al. (2016) identified a heterozygous c.1270C-T transition (c.1270C-T, NM_001077350) in the NPRL3 gene, resulting in an arg424-to-ter (R424X) substitution. 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. At least 1 unaffected family member carried the mutation, consistent with incomplete penetrance. Analysis of patient cells showed that the mutant transcript was subject to nonsense-mediated mRNA decay, consistent with haploinsufficiency. Brain sample from 1 of the patients, who had focal cortical dysplasia, showed hyperactivation of the mTOR pathway in normal and dysmorphic neurons. These findings suggested that the NPRL3 mutation resulted in a loss of function of the GATOR1 complex. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NPRL3, 1-BP DEL, 1070C
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs886037962,
|
|
|
|
|
|
|
|
ClinVar: RCV000241093
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 members of a 3-generation Swiss family (family G) with familial focal epilepsy with variable foci-3 (FFEVF3; 617118), Weckhuysen et al. (2016) identified a heterozygous 1-bp deletion (c.1070delC, NM_001077350) in the NPRL3 gene, resulting in a frameshift and premature termination (Pro357HisfsTer56). 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. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NPRL3, 1-BP DEL, 349G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1900088045,
|
|
|
|
|
|
|
|
ClinVar: RCV001067555, RCV003159179
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 133 members of an Old Order Mennonite pedigree with familial focal epilepsy with variable foci-3 (FFEVF3; 617118), Iffland et al. (2022) identified heterozygosity for a 1-bp deletion (c.349delG) in the NPRL3 gene, predicted to result in a frameshift and premature termination (Glu117LysfsTer). The mutation was identified in each patient by whole-exome sequencing, targeted NPRL3 variant testing, or an extended carrier test targeted for the Older Order Amish and Mennonite communities. Pedigree analysis demonstrated that all of the mutation carriers traced back to a single founder. Of the 133 patients, 48 had a history of seizures and 85 had no history of seizures. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
|
|
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<div>
|
|
<br />
|
|
</div>
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|
</div>
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</div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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<div>
|
|
<ol>
|
|
|
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<li>
|
|
<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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Iffland, P. H., Everett, M. E., Cobb-Pitstick, K. M., Bowser, L. E., Barnes, A. E., Babus, J. K., Romanowski, A. J., Baybis, M., Elziny, S., Puffenberger, E. G., Gonzaga-Jauregui, C., Poulopoulos, A., Carson, V. J., Crino, P. B.
|
|
<strong>NPRL3 loss alters neuronal morphology, mTOR localization, cortical lamination and seizure threshold.</strong>
|
|
Brain 145: 3872-3885, 2022.
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[PubMed: 35136953]
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[Full Text: https://doi.org/10.1093/brain/awac044]
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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.
|
|
<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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Sim, J. C., Scerri, T., Fanjul-Fernandez, M., Riseley, J. R., Gillies, G., Pope, K., van Roozendaal, H., Heng, J. I., Mandelstam, S. A., McGilivray, G., MacGregor, D., Kannan, L., Maixner, W., Harvey, A. S., Amor, D. J., Delatycki, M. B., Crino, P. B., Bahlo, M., Lockhart, P. J., Leventer, R. J.
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<strong>Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3.</strong>
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[PubMed: 26285051]
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[Full Text: https://doi.org/10.1002/ana.24502]
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Vyas, P., Vickers, M. A., Picketts, D. J., Higgs, D. R.
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<strong>Conservation of position and sequence of a novel, widely expressed gene containing the major human alpha-globin regulatory element.</strong>
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Genomics 29: 679-689, 1995.
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[PubMed: 8575760]
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[Full Text: https://doi.org/10.1006/geno.1995.9951]
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Vyas, P., Vickers, M. A., Simmons, D. L., Ayyub, H., Craddock, C. F., Higgs, D. R.
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<strong>Cis-acting sequences regulating expression of the human alpha-globin cluster lie within constitutively open chromatin.</strong>
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Cell 69: 781-793, 1992.
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[PubMed: 1591777]
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[Full Text: https://doi.org/10.1016/0092-8674(92)90290-s]
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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: 27173016]
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[Full Text: https://doi.org/10.1111/epi.13391]
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Hilary J. Vernon - updated : 03/01/2023<br>Ada Hamosh - updated : 08/27/2018<br>Patricia A. Hartz - updated : 01/29/2018<br>Cassandra L. Kniffin - updated : 09/20/2016<br>Ada Hamosh - updated : 07/07/2014
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Alan F. Scott : 11/7/1995
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alopez : 09/20/2023<br>mgross : 03/30/2023<br>carol : 03/02/2023<br>carol : 03/01/2023<br>alopez : 08/27/2018<br>mgross : 01/29/2018<br>mgross : 03/30/2017<br>carol : 09/22/2016<br>carol : 09/21/2016<br>carol : 09/21/2016<br>ckniffin : 09/20/2016<br>alopez : 07/07/2014<br>carol : 3/24/2014<br>alopez : 4/7/2009<br>joanna : 5/8/1998<br>terry : 11/13/1995<br>mark : 11/7/1995
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