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Entry
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- *605284 - TSC COMPLEX SUBUNIT 1; TSC1
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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">*605284</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</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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<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/605284">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel 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=ENSG00000165699;t=ENST00000298552" 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=7248" 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=605284" 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=ENSG00000165699;t=ENST00000298552" 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_000368,NM_001162426,NM_001162427,NM_001362177,NM_001406592,NM_001406593,NM_001406594,NM_001406595,NM_001406596,NM_001406597,NM_001406598,NM_001406599,NM_001406600,NM_001406601,NM_001406602,NM_001406603,NM_001406604,NM_001406605,NM_001406606,NM_001406607,NM_001406608,NM_001406609,NM_001406610,NM_001406611,NM_001406612,NM_001406613,NM_001406614,NM_001406615,NM_001406616,NM_001406617,NM_001406618,NM_001406619,NM_001406620,NM_001406621,NM_001406622,NM_001406623,NM_001406624,NM_001406625,NM_001406626,NM_001406627,NM_001406628,NM_001406629,NM_001406630,NR_176214,NR_176215,NR_176216,NR_176217,NR_176218,XM_011518979" 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_000368" 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=605284" 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=05594&isoform_id=05594_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/TSC1" 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/1663702,2331281,4507693,7407185,9297077,9937300,13094959,14328910,14328912,14328914,28839749,47123283,62005845,80476713,111309173,119608427,151935435,221041742,221042826,221044412,241666462,241666464,608785513,767958188,1168016834,1168016836,1375023171,1391906933,1391906935,2240436578,2240436588,2240436592,2240436598,2240436604,2240436606,2240436612,2240436623,2240436627,2240436633,2240436635,2240436643,2240436651,2240436665,2240436685,2240436691,2240436699,2240436701,2240436707,2240436711,2240436716,2240436726,2240436728,2240436735,2240436739,2240436743,2240436747,2240436753,2240436755,2240436757,2240436775,2240436779,2240436783,2240436787,2240436793,2240436797,2240436803,2240897263,2240897356,2462626253" 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/Q92574" 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=7248" 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=ENSG00000165699;t=ENST00000298552" 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=TSC1" 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=TSC1" 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+7248" 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/TSC1" 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:7248" 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/7248" 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=chr9&hgg_gene=ENST00000298552.9&hgg_start=132891349&hgg_end=132945378&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:12362" 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:12362" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=605284[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=605284[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/TSC1/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/ENSG00000165699" 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=TSC1" 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=TSC1" 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=TSC1" 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="http://www.LOVD.nl/TSC1" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=TSC1&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/PA37034" 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:12362" 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/FBgn0026317.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:1929183" 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/TSC1#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:1929183" 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/7248/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://omia.org/OMIA002427/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=7248" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-3404" 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="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" 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="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</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="mimCellLinesLinksFold" 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://catalog.coriell.org/Search?q=OmimNum:605284" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</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:7248" 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=TSC1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 73017001<br />
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<strong>ICD10CM:</strong> J84.81<br />
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<strong>ICD9CM:</strong> 516.4<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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605284
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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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TSC COMPLEX SUBUNIT 1; TSC1
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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>
|
|
<span class="mim-font">
|
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TSC1 GENE<br />
|
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HAMARTIN
|
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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=TSC1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TSC1</a></em></strong>
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/9/601?start=-3&limit=10&highlight=601">9q34.13</a>
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr9:132891349-132945378&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'})">9:132,891,349-132,945,378</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
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Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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<span class="hidden-sm hidden-xs pull-right">
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>The TSC1 gene encodes hamartin, a protein that interacts with tuberin (TSC2; <a href="/entry/191092">191092</a>) to form a protein complex that inhibits signal transduction to the downstream effectors of the mammalian target of rapamycin (MTOR; <a href="/entry/601231">601231</a>) (<a href="#27" class="mim-tip-reference" title="Inoki, K., Li, Y., Zhu, T., Wu, J., Guan, K.-L. <strong>TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling.</strong> Nature Cell Biol. 4: 648-657, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12172553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12172553</a>] [<a href="https://doi.org/10.1038/ncb839" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12172553">Inoki et al., 2002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12172553" 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>As part of a comprehensive strategy to identify the gene mutant in tuberous sclerosis-1 (<a href="/entry/191100">191100</a>), <a href="#60" class="mim-tip-reference" title="van Slegtenhorst, M., de Hoogt, R., Hermans, C., Nellist, M., Janssen, B., Verhoef, S., Lindhout, D., van den Ouweland, A., Halley, D., Young, J., Burley, M., Jeremiah, S., and 29 others. <strong>Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34.</strong> Science 277: 805-808, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9242607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9242607</a>] [<a href="https://doi.org/10.1126/science.277.5327.805" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9242607">van Slegtenhorst et al. (1997)</a> developed an overlapping contig of clones from the 1.4-Mb TSC1 region on chromosome 9. Several techniques showed the region to be gene-rich, with at least 30 genes in a 900-kb segment. They identified 142 exons and 13 genes between D9S1199 and D9S114. The authors PCR-amplified putative and confirmed exons in a set of 60 DNA samples from 40 sporadic tuberous sclerosis cases and 20 unrelated familial tuberous sclerosis patients showing linkage to 9q34. <a href="#60" class="mim-tip-reference" title="van Slegtenhorst, M., de Hoogt, R., Hermans, C., Nellist, M., Janssen, B., Verhoef, S., Lindhout, D., van den Ouweland, A., Halley, D., Young, J., Burley, M., Jeremiah, S., and 29 others. <strong>Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34.</strong> Science 277: 805-808, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9242607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9242607</a>] [<a href="https://doi.org/10.1126/science.277.5327.805" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9242607">Van Slegtenhorst et al. (1997)</a> identified mutations in an exon that was part of a transcriptional unit identified by earlier gene discovery efforts (<a href="#43" class="mim-tip-reference" title="Nagase, T., Seki, N., Ishikawa, K., Ohira, M., Kawarabayasi, Y., Ohara, O., Tanaka, A., Kotani, H., Miyajima, N., Nomura, N. <strong>Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain.</strong> DNA Res. 3: 321-329, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9039502/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9039502</a>] [<a href="https://doi.org/10.1093/dnares/3.5.321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9039502">Nagase et al., 1996</a>). The predicted TSC1 protein, which was called 'hamartin' by <a href="#60" class="mim-tip-reference" title="van Slegtenhorst, M., de Hoogt, R., Hermans, C., Nellist, M., Janssen, B., Verhoef, S., Lindhout, D., van den Ouweland, A., Halley, D., Young, J., Burley, M., Jeremiah, S., and 29 others. <strong>Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34.</strong> Science 277: 805-808, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9242607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9242607</a>] [<a href="https://doi.org/10.1126/science.277.5327.805" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9242607">van Slegtenhorst et al. (1997)</a>, consists of 1,164 amino acids and has a calculated mass of 130 kD. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9039502+9242607" 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>The TSC1 gene consists of 23 exons, of which the last 21 contain coding sequence and the second is alternatively spliced (<a href="#60" class="mim-tip-reference" title="van Slegtenhorst, M., de Hoogt, R., Hermans, C., Nellist, M., Janssen, B., Verhoef, S., Lindhout, D., van den Ouweland, A., Halley, D., Young, J., Burley, M., Jeremiah, S., and 29 others. <strong>Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34.</strong> Science 277: 805-808, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9242607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9242607</a>] [<a href="https://doi.org/10.1126/science.277.5327.805" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9242607">van Slegtenhorst et al., 1997</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9242607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Cheadle, J. P., Dobbie, L., Idziaszczyk, S., Hodges, A. K., Smith, A. J. H., Sampson, J. R., Young, J. <strong>Genomic organization and comparative analysis of the mouse tuberous sclerosis 1 (Tsc1) locus.</strong> Mammalian Genome 11: 1135-1138, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11130985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11130985</a>] [<a href="https://doi.org/10.1007/s003350010203" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11130985">Cheadle et al. (2000)</a> described the genomic organization of the mouse Tsc1 locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11130985" 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>Hamartin (TSC1), the protein that is defective in tuberous sclerosis-1, has no significant homology to tuberin (TSC2; <a href="/entry/191092">191092</a>), the protein defective in tuberous sclerosis-2, which is a putative GTPase-activating protein for RAP1 (see <a href="/entry/600278">600278</a>) and RAB5 (<a href="/entry/179512">179512</a>). <a href="#61" class="mim-tip-reference" title="van Slegtenhorst, M., Nellist, M., Nagelkerken, B., Cheadle, J., Snell, R., van den Ouweland, A., Reuser, A., Sampson, J., Halley, D., van der Sluijs, P. <strong>Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products.</strong> Hum. Molec. Genet. 7: 1053-1057, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9580671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9580671</a>] [<a href="https://doi.org/10.1093/hmg/7.6.1053" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9580671">Van Slegtenhorst et al. (1998)</a> showed that hamartin and tuberin associate physically in vivo, however, and that the interaction is mediated by predicted coiled-coil domains. The data suggested to the authors that hamartin and tuberin function in the same complex rather than in separate pathways. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9580671" 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="#8" class="mim-tip-reference" title="Benvenuto, G., Li, S., Brown, S. J., Braverman, R., Vass, W. C., Cheadle, J. P., Halley, D. J. J., Sampson, J. R., Wienecke, R., DeClue, J. E. <strong>The tuberous sclerosis-1 (TSC1) gene product hamartin suppresses cell growth and augments the expression of the TSC2 product tuberin by inhibiting its ubiquitination.</strong> Oncogene 19: 6306-6316, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175345</a>] [<a href="https://doi.org/10.1038/sj.onc.1204009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175345">Benvenuto et al. (2000)</a> showed that overexpression of the TSC1 gene in rat fibroblasts inhibits growth and causes changes in cell morphology. Growth inhibition was associated with an increase in the endogenous level of tuberin. As overexpression of tuberin inhibits cell growth, and hamartin is known to bind tuberin, these results suggested that hamartin stabilizes tuberin and that this contributes to the inhibition of cell growth. The stabilization was explained by the finding that tuberin is highly ubiquitinated in cells, while the fraction of tuberin that is bound to hamartin is not ubiquitinated. Coexpression of tuberin stabilized hamartin, which is weakly ubiquitinated, in transiently transfected cells. The amino-terminal two-thirds of tuberin was responsible for its ubiquitination and for stabilization of hamartin. A mutant of tuberin from a patient with a missense mutation of the TSC2 gene, N1658K, was also highly ubiquitinated, and was unable to stabilize hamartin. <a href="#8" class="mim-tip-reference" title="Benvenuto, G., Li, S., Brown, S. J., Braverman, R., Vass, W. C., Cheadle, J. P., Halley, D. J. J., Sampson, J. R., Wienecke, R., DeClue, J. E. <strong>The tuberous sclerosis-1 (TSC1) gene product hamartin suppresses cell growth and augments the expression of the TSC2 product tuberin by inhibiting its ubiquitination.</strong> Oncogene 19: 6306-6316, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175345</a>] [<a href="https://doi.org/10.1038/sj.onc.1204009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175345">Benvenuto et al. (2000)</a> concluded that hamartin is a growth inhibitory protein whose biologic effect is probably dependent on its interaction with tuberin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11175345" 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="#26" class="mim-tip-reference" title="Hodges, A. K., Li, S., Maynard, J., Parry, L., Braverman, R., Cheadle, J. P., DeClue, J. E., Sampson, J. R. <strong>Pathological mutations in TSC1 and TSC2 disrupt the interaction between hamartin and tuberin.</strong> Hum. Molec. Genet. 10: 2899-2905, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11741833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11741833</a>] [<a href="https://doi.org/10.1093/hmg/10.25.2899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11741833">Hodges et al. (2001)</a> used a series of hamartin and tuberin constructs to assay for interaction in the yeast 2-hybrid system. Hamartin (amino acids 302-430) and tuberin (amino acids 1-418) interacted strongly with one another. A region of tuberin encoding a putative coiled-coil (amino acids 346-371) was necessary but not sufficient to mediate the interaction with hamartin, as more N-terminal residues were also required. A region of hamartin (amino acids 719-998) predicted to encode coiled-coils was capable of oligomerization but was not important for the interaction with tuberin. Subtle, non-truncating mutations identified in patients with tuberous sclerosis and located within the putative binding regions of hamartin or tuberin abolished or dramatically reduced interaction of the proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11741833" 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="#42" class="mim-tip-reference" title="Miloloza, A., Rosner, M., Nellist, M., Halley, D., Bernaschek, G., Hengstschlager, M. <strong>The TSC1 gene product, hamartin, negatively regulates cell proliferation.</strong> Hum. Molec. Genet. 9: 1721-1727, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10915759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10915759</a>] [<a href="https://doi.org/10.1093/hmg/9.12.1721" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10915759">Miloloza et al. (2000)</a> showed that expression of hamartin, assayed by immunoblot analyses, is high in G0-arrested cells, although it is expressed throughout the entire ongoing cell cycle. In addition, ectopic expression of high levels of hamartin attenuated cellular proliferation. The authors proposed that hamartin affects cell proliferation via deregulation of G1 phase. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10915759" 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>Activated ezrin (<a href="/entry/123900">123900</a>), radixin (<a href="/entry/179410">179410</a>), and moesin (<a href="/entry/309845">309845</a>) (ERM) family proteins promote linkages between integral membrane proteins and cytoskeleton proteins, such as F-actin (see ACTA1; <a href="/entry/102610">102610</a>). In the inactive form, the N and C termini of the ERM protein interact, masking their membrane- and actin-interacting activities, respectively. Activation of ERM proteins requires RHO (see ARHA; <a href="/entry/165390">165390</a>), which induces a cascade that results in the phosphorylation of threonine in the C terminus of the ERM protein and causes the intramolecular bond between the N and C termini to dissociate (<a href="#19" class="mim-tip-reference" title="Fukuhara, S., Gutkind, J. S. <strong>A new twist for the tumour suppressor hamartin.</strong> Nature Cell Biol. 2: E76-E78, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10806489/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10806489</a>] [<a href="https://doi.org/10.1038/35010506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10806489">Fukuhara and Gutkind, 2000</a>). <a href="#37" class="mim-tip-reference" title="Lamb, R. F., Roy, C., Diefenbach, T. J., Vinters, H. V., Johnson, M. W., Jay, D. G., Hall, A. <strong>The TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho.</strong> Nature Cell Biol. 2: 281-286, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10806479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10806479</a>] [<a href="https://doi.org/10.1038/35010550" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10806479">Lamb et al. (2000)</a> used yeast 2-hybrid analysis to screen a mouse fibroblast cDNA library with ezrin as bait. Slot blot analysis, immunoprecipitation, immunofluorescence microscopy, and mutation analysis indicated that the N terminus of ezrin interacts with the C terminus of hamartin, whereas it interacts only weakly with merlin (<a href="/entry/607379">607379</a>) and not at all with giantin (<a href="/entry/602500">602500</a>). Hamartin also interacted with the N termini of radixin and moesin. Immunofluorescence microscopy showed that hamartin interacts with F-actin, suggesting that hamartin may be a direct binding partner for ERM proteins. Inactivation of hamartin by microscale chromophore-assisted laser inactivation (micro-CALI) or by antisense hamartin caused a marked retraction of the affected area of endothelial cell membranes, loss of adhesion, and cell rounding. Cell adhesion could be restored by injection of active RHO. Expression of hamartin in cells without organized actin filaments promoted the assembly of focal adhesions and the assembly of actin stress fibers. This activity required RHO and residues 145 to 510 of hamartin. Introduction of a C-terminal fragment of hamartin inhibited the assembly of actin stress fibers by lysophosphatidic acid, a serum factor that activates RHO, suggesting that the interaction of hamartin with ERM proteins is required upstream of RHO. <a href="#37" class="mim-tip-reference" title="Lamb, R. F., Roy, C., Diefenbach, T. J., Vinters, H. V., Johnson, M. W., Jay, D. G., Hall, A. <strong>The TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho.</strong> Nature Cell Biol. 2: 281-286, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10806479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10806479</a>] [<a href="https://doi.org/10.1038/35010550" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10806479">Lamb et al. (2000)</a> proposed that loss or perturbation of hamartin function leads to loss of adhesion to the cellular matrix and initiates the development of TSC hamartomas <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10806489+10806479" 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="#56" class="mim-tip-reference" title="Tapon, N., Ito, N., Dickson, B. J., Treisman, J. E., Hariharan, I. K. <strong>The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation.</strong> Cell 105: 345-355, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11348591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11348591</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00332-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11348591">Tapon et al. (2001)</a> characterized mutations in the Drosophila Tsc1 and Tsc2 (gigas) genes. Inactivating mutations in either gene caused an identical phenotype characterized by enhanced growth and increased cell size with no change in ploidy. Overall, mutant cells spent less time in G1. Coexpression of both Tsc1 and Tsc2 restricted tissue growth and reduced cell size and cell proliferation. This phenotype was modulated by manipulations in cyclin levels. In postmitotic mutant cells, levels of cyclin E (<a href="/entry/123837">123837</a>) and cyclin A (<a href="/entry/123835">123835</a>) were elevated. This correlated with a tendency for these cells to reenter the cell cycle inappropriately, as is observed in the human lesions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11348591" 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="#49" class="mim-tip-reference" title="Potter, C. J., Huang, H., Xu, T. <strong>Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size.</strong> Cell 105: 357-368, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11348592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11348592</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00333-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11348592">Potter et al. (2001)</a> isolated a mutation in the Drosophila Tsc1 gene. Cells mutant for Tsc1 were dramatically increased in size yet differentiated normally. Organ size was also increased in tissues that contained a majority of mutant cells. Clones of Tsc1 mutant cells in the imaginal discs underwent additional divisions but retained normal ploidy. <a href="#49" class="mim-tip-reference" title="Potter, C. J., Huang, H., Xu, T. <strong>Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size.</strong> Cell 105: 357-368, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11348592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11348592</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00333-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11348592">Potter et al. (2001)</a> also showed that the Tsc1 protein binds to Drosophila Tsc2 in vitro. Overexpression of Tsc1 or Tsc2 alone in the wing and eye had no effect, but co-overexpression led to a decrease in cell size, cell number, and organ size. Genetic epistasis data were consistent with a model in which Tsc1 and Tsc2 function together in the insulin (INS; <a href="/entry/176730">176730</a>) signaling pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11348592" 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="#27" class="mim-tip-reference" title="Inoki, K., Li, Y., Zhu, T., Wu, J., Guan, K.-L. <strong>TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling.</strong> Nature Cell Biol. 4: 648-657, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12172553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12172553</a>] [<a href="https://doi.org/10.1038/ncb839" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12172553">Inoki et al. (2002)</a> showed that the Tsc1-Tsc2 complex inhibits the mammalian target of rapamycin (MTOR; <a href="/entry/601231">601231</a>), leading to inhibition of p70 ribosomal S6 kinase-1 (<a href="/entry/608938">608938</a>) and activation of eukaryotic translation initiation factor 4E-binding protein-1 (EIF4EBP1; <a href="/entry/602223">602223</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12172553" 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="Astrinidis, A., Senapedis, W., Henske, E. P. <strong>Hamartin, the tuberous sclerosis complex 1 gene product, interacts with polo-like kinase 1 in a phosphorylation-dependent manner.</strong> Hum. Molec. Genet. 15: 287-297, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16339216/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16339216</a>] [<a href="https://doi.org/10.1093/hmg/ddi444" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16339216">Astrinidis et al. (2006)</a> found that endogenous polo-like kinase-1 (PLK1; <a href="/entry/602098">602098</a>) associated with the hamartin-tuberin complex in several human and nonhuman cell lines and that the complex localized to centrosomes. Phosphorylated hamartin interacted with PLK1 independent of tuberin, and the interaction required thr310 of hamartin. Hamartin negatively regulated the protein levels of PLK1 and regulated centrosome number in an MTOR-dependent manner. Hamartin-deficient mouse embryonic fibroblasts had an increased number of centrosomes and a mitotic defect leading to increased DNA content, and these defects were reversed by rapamycin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16339216" 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>Loss of the TSC genes leads to constitutive activation of MTOR and downstream signaling elements, resulting in tumor development, neurologic disorders, and severe insulin/IGF1 (<a href="/entry/147440">147440</a>) resistance. <a href="#47" class="mim-tip-reference" title="Ozcan, U., Ozcan, L., Yilmaz, E., Duvel, K., Sahin, M., Manning, B. D., Hotamisligil, G. S. <strong>Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis.</strong> Molec. Cell 29: 541-551, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18342602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18342602</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18342602[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.molcel.2007.12.023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18342602">Ozcan et al. (2008)</a> found that loss of TSC1 or TSC2 in cell lines and mouse or human tumors caused endoplasmic reticulum (ER) stress and activated the unfolded protein response. The resulting ER stress played a significant role in the MTOR-mediated negative feedback inhibition of insulin action and increased the vulnerability to apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18342602" 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="#15" class="mim-tip-reference" title="Choi, Y.-J., Di Nardo, A., Kramvis, I., Meikle, L., Kwiatkowski, D. J., Sahin, M., He, X. <strong>Tuberous sclerosis complex proteins control axon formation.</strong> Genes Dev. 22: 2485-2495, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18794346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18794346</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18794346[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/10.1101/gad.1685008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18794346">Choi et al. (2008)</a> showed that Tsc1 and Tsc2 had critical functions in axon formation and growth in mouse. Overexpression of Tsc1/Tsc2 suppressed axon formation, whereas lack of Tsc1 or Tsc2 induced ectopic axons in vitro and in mouse brain. Tsc2 was phosphorylated and inhibited in axons, but not dendrites. Inactivation of Tsc1/Tsc2 promoted axonal growth, at least in part, via upregulation of neuronal polarity Sad kinase (see BRSK2; <a href="/entry/609236">609236</a>), which was also elevated in cortical tubers of a TSC patient. <a href="#15" class="mim-tip-reference" title="Choi, Y.-J., Di Nardo, A., Kramvis, I., Meikle, L., Kwiatkowski, D. J., Sahin, M., He, X. <strong>Tuberous sclerosis complex proteins control axon formation.</strong> Genes Dev. 22: 2485-2495, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18794346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18794346</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18794346[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/10.1101/gad.1685008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18794346">Choi et al. (2008)</a> concluded that TSC1 and TSC2 have critical roles in neuronal polarity, and that a common pathway regulates polarization and growth in neurons and cell size in other tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18794346" 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>To test for the role of intrinsic impediments to axon regrowth, <a href="#48" class="mim-tip-reference" title="Park, K. K., Liu, K., Hu, Y., Smith, P. D., Wang, C., Cai. B., Xu, B., Connolly, L., Kramvis, I., Sahin, M., He, Z. <strong>Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway.</strong> Science 322: 963-966, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18988856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18988856</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18988856[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.1161566" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18988856">Park et al. (2008)</a> analyzed cell growth control genes using a virus-assisted in vivo conditional knockout approach. In wildtype adult mice, mTOR activity was suppressed and new protein synthesis was impaired in axotomized retinal ganglion cells, which may have contributed to the regeneration failure. Reactivating this pathway by conditional knockout of TSC1, a negative regulator of the mTOR pathway, led to axon regeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18988856" 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="#17" class="mim-tip-reference" title="DiBella, L. M., Park, A., Sun, Z. <strong>Zebrafish Tsc1 reveals functional interactions between the cilium and the TOR pathway.</strong> Hum. Molec. Genet. 18: 595-606, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19008302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19008302</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19008302[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/hmg/ddn384" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19008302">DiBella et al. (2009)</a> showed that morpholino knockdown of zebrafish Tsc1a led to a ciliary phenotype including kidney cyst formation and left-right asymmetry defects. Tsc1a localized to the Golgi, but morpholinos against it, nonetheless, acted synthetically with ciliary genes in producing kidney cysts. Consistent with a role of the cilium in the same pathway as Tsc genes, the TOR (FRAP1; <a href="/entry/601231">601231</a>) pathway was found to be aberrantly activated in ciliary mutants, resembling the effect of Tsc1a knockdown. Kidney cyst formation in ciliary mutants was blocked by the Tor inhibitor rapamycin. <a href="#17" class="mim-tip-reference" title="DiBella, L. M., Park, A., Sun, Z. <strong>Zebrafish Tsc1 reveals functional interactions between the cilium and the TOR pathway.</strong> Hum. Molec. Genet. 18: 595-606, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19008302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19008302</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19008302[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/hmg/ddn384" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19008302">DiBella et al. (2009)</a> suggested a signaling network between the cilium and the TOR pathway wherein ciliary signals can feed into the TOR pathway and where Tsc1a may regulate the length of the cilium itself. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19008302" 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="#24" class="mim-tip-reference" title="Hartman, T. R., Liu, D., Zilfou, J. T., Robb, V., Morrison, T., Watnick, T., Henske, E. P. <strong>The tuberous sclerosis proteins regulate formation of the primary cilium via a rapamycin-insensitive and polycystin 1-independent pathway.</strong> Hum. Molec. Genet. 18: 151-163, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18845692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18845692</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18845692[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/hmg/ddn325" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18845692">Hartman et al. (2009)</a> reported that hamartin (TSC1) localized to the basal body of the primary cilium, and that Tsc1-null and Tsc2-null mouse embryonic fibroblasts (MEFs) were significantly more likely to contain a primary cilium than wildtype controls. In addition, the cilia of Tsc1- and Tsc2-null MEFs were 17 to 27% longer than cilia from wildtype MEFs. Enhanced ciliary formation in the Tsc1- and Tsc2-null MEFs was not abrogated by rapamycin, which suggests an mTOR-independent mechanism. Polycystin-1 (PC1; see <a href="/entry/601313">601313</a>) has been found to interact with TSC2, but Pkd1-null MEFs did not have enhanced ciliary formation. While activation of mTOR has been observed in renal cysts from ADPKD patients, Pkd1-null MEFs did not have evidence of constitutive mTOR activation, thereby underscoring the independent functions of the TSC proteins and PC1 in regulation of primary cilia and mTOR. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18845692" 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="#67" class="mim-tip-reference" title="Zhang, Y., Nicholatos, J., Dreier, J. R., Ricoult, S. J. H., Widenmaier, S. B., Hotamisligil, G. S., Kwiatkowski, D. J., Manning, B. D. <strong>Coordinated regulation of protein synthesis and degradation by mTORC1.</strong> Nature 513: 440-443, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25043031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25043031</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25043031[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/nature13492" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25043031">Zhang et al. (2014)</a> showed that as well as increasing protein synthesis, mTORC1 activation in mouse and human cells also promotes an increased capacity for protein degradation. Cells with activated mTORC1 exhibited elevated levels of intact and active proteasomes through a global increase in the expression of genes encoding proteasome subunits. The increase in proteasome gene expression, cellular proteasome content, and rates of protein turnover downstream of mTORC1 were all dependent on induction of the transcription factor NRF1 (NFE2L1; <a href="/entry/163260">163260</a>). Genetic activation of mTORC1 through loss of the tuberous sclerosis complex tumor suppressors TSC1 or TSC2 (<a href="/entry/191092">191092</a>), or physiologic activation of mTORC1 in response to growth factors or feeding, resulted in increased NRF1 expression in cells and tissues. <a href="#67" class="mim-tip-reference" title="Zhang, Y., Nicholatos, J., Dreier, J. R., Ricoult, S. J. H., Widenmaier, S. B., Hotamisligil, G. S., Kwiatkowski, D. J., Manning, B. D. <strong>Coordinated regulation of protein synthesis and degradation by mTORC1.</strong> Nature 513: 440-443, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25043031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25043031</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25043031[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/nature13492" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25043031">Zhang et al. (2014)</a> found that this NRF1-dependent elevation in proteasome levels serves to increase the intracellular pool of amino acids, which thereby influences rates of new protein synthesis. The authors therefore concluded that mTORC1 signaling increases the efficiency of proteasome-mediated protein degradation for both quality control and as a mechanism to supply substrate for sustained protein synthesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25043031" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Tuberous Sclerosis</em></strong></p><p>
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<a href="#60" class="mim-tip-reference" title="van Slegtenhorst, M., de Hoogt, R., Hermans, C., Nellist, M., Janssen, B., Verhoef, S., Lindhout, D., van den Ouweland, A., Halley, D., Young, J., Burley, M., Jeremiah, S., and 29 others. <strong>Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34.</strong> Science 277: 805-808, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9242607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9242607</a>] [<a href="https://doi.org/10.1126/science.277.5327.805" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9242607">Van Slegtenhorst et al. (1997)</a> screened exons in the 1.4-Mb TSC1 region on chromosome 9 for mutations in tuberous sclerosis patients. One of the exons of the TSC1 gene screened for mutations demonstrated mobility shifts in heteroduplex analysis of samples from 10 of the 60 patient samples. Sequence analysis revealed 7 small frameshifting mutations (e.g., <a href="#0001">605284.0001</a>), 1 nonsense mutation (<a href="#0002">605284.0002</a>), 1 missense mutation (<a href="#0003">605284.0003</a>), and 1 polymorphism that did not change the encoded amino acid. It was exon 15 in which the high frequency of mutations was found on the initial screen. Exon 15 is 559 bp long and represents 16% of the coding region. Mutation was found in exon 15 in 8 of 55 tuberous sclerosis families (15%) showing linkage to 9q34 and in only 15 of 607 (2.5%) of sporadic patients or families uninformative for linkage. A screen for mutations in all coding exons in 20 familial cases and 152 sporadic patients yielded 8 mutations in each group (40% and 5%, respectively). Of 32 distinct mutations found in TSC1, 30 were truncating, and 1 mutation (2105delAAAG; <a href="#0001">605284.0001</a>) was seen in 6 apparently unrelated patients. In one of these 6, a somatic mutation in the wildtype allele was found in a tuberous sclerosis-associated renal carcinoma, which suggested that hamartin acts as a tumor suppressor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9242607" 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="#30" class="mim-tip-reference" title="Jones, A. C., Daniells, C. E., Snell, R. G., Tachataki, M., Idziaszczyk, S. A., Krawczak, M., Sampson, J. R., Cheadle, J. P. <strong>Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis.</strong> Hum. Molec. Genet. 6: 2155-2161, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9328481/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9328481</a>] [<a href="https://doi.org/10.1093/hmg/6.12.2155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9328481">Jones et al. (1997)</a> comprehensively defined the TSC1 mutation spectrum in 171 sequentially ascertained, unrelated TSC patients by SSCP and heteroduplex analysis of all 21 coding exons, and by assaying a restriction fragment spanning the whole locus. Mutations were identified in 9 of 24 familial cases, but in only 13 of 147 sporadic cases. In contrast, a limited screen revealed mutations in the TSC2 gene in 2 of the 24 familial cases and in 45 of the 147 sporadic cases. Thus, TSC1 mutations were significantly underrepresented among sporadic cases. Both large deletions and missense mutations were common at the TSC2 locus, whereas most TSC1 mutations were small truncated lesions. Mental retardation was significantly less frequent among carriers of TSC1 mutations than TSC2 mutations (odds ratio, 5.54 for sporadic cases only; 6.78 +/- 1.54 when a single randomly selected patient per multigeneration family was also included). No correlation between mental retardation and the type of mutation was found. <a href="#30" class="mim-tip-reference" title="Jones, A. C., Daniells, C. E., Snell, R. G., Tachataki, M., Idziaszczyk, S. A., Krawczak, M., Sampson, J. R., Cheadle, J. P. <strong>Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis.</strong> Hum. Molec. Genet. 6: 2155-2161, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9328481/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9328481</a>] [<a href="https://doi.org/10.1093/hmg/6.12.2155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9328481">Jones et al. (1997)</a> concluded that there is a reduced risk of mental retardation in tuberous sclerosis-1 as opposed to tuberous sclerosis-2 and that consequent ascertainment bias, at least in part, explains the relative paucity of TSC1 mutations in sporadic TSC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9328481" 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="#34" class="mim-tip-reference" title="Kwiatkowska, J., Jozwiak, S., Hall, F., Henske, E. P., Haines, J. L., McNamara, P., Braiser, J., Wigowska-Sowinska, J., Kasprzyk-Obara, J., Short, M. P., Kwiatkowski, D. J. <strong>Comprehensive mutational analysis of the TSC1 gene: observations on frequency of mutation, associated features, and nonpenetrance.</strong> Ann. Hum. Genet. 62: 277-285, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9924605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9924605</a>] [<a href="https://doi.org/10.1046/j.1469-1809.1998.6240277.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9924605">Kwiatkowska et al. (1998)</a> performed a comprehensive analysis for mutations in the TSC1 gene using Southern blot analysis, and SSCP and heteroduplex analysis of amplified exons in 13 families with genetic linkage to the TSC1 region, 22 small families without linkage information, and 126 sporadic patients. Seventeen unique mutations were identified in 21 patients. Mutations were found in 7 of 13 (54%) tuberous sclerosis-1-linked families, in 1 of 22 (5%) small families without linkage, and in 13 of 126 (10%) sporadic cases. The mutations were all chain-terminating, with 14 small deletions, 1 small insertion, and 6 nonsense mutations. Twelve of the 21 mutations were previously reported by <a href="#60" class="mim-tip-reference" title="van Slegtenhorst, M., de Hoogt, R., Hermans, C., Nellist, M., Janssen, B., Verhoef, S., Lindhout, D., van den Ouweland, A., Halley, D., Young, J., Burley, M., Jeremiah, S., and 29 others. <strong>Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34.</strong> Science 277: 805-808, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9242607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9242607</a>] [<a href="https://doi.org/10.1126/science.277.5327.805" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9242607">van Slegtenhorst et al. (1997)</a>, and 9 were new. In families with mutations, all individuals carrying a mutation met formal diagnostic criteria for tuberous sclerosis, apart from a 3-year-old girl who had inherited a deletion mutation and who had no seizures, normal intelligence, normal abdominal ultrasound, and hypomelanotic macules only on physical examination. Her 7-year-old sister with the same TSC1 mutation had severe mental retardation. They found no significant difference in the incidence and severity of mental retardation in the 13 sporadic patients with TSC1 mutations versus the entire sporadic cohort. The observation indicated that TSC1 mutations are all inactivating, suggested that tuberous sclerosis-1 occurs in only 15 to 20% of the sporadic tuberous sclerosis population, and demonstrated that presymptomatic tuberous sclerosis occurs. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9924605+9242607" 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="#31" class="mim-tip-reference" title="Jones, A. C., Shyamsundar, M. M., Thomas, M. W., Maynard, J., Idziaszczyk, S., Tomkins, S., Sampson, J. R., Cheadle, J. P. <strong>Comprehensive mutation analysis of TSC1 and TSC2--and phenotypic correlations in 150 families with tuberous sclerosis.</strong> Am. J. Hum. Genet. 64: 1305-1315, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10205261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10205261</a>] [<a href="https://doi.org/10.1086/302381" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10205261">Jones et al. (1999)</a> reported a comprehensive mutation analysis of the TSC1 and TSC2 genes in a cohort of 150 unrelated tuberous sclerosis patients and their families, using heteroduplex and SSCP analysis of all coding exons, and pulsed field gel electrophoresis, Southern blot analysis, and long PCR to screen for large rearrangements. Mutations were detected in 120 (80%) of the 150 cases, affecting the TSC1 gene in 22 cases and the TSC2 gene in 98 cases. TSC1 mutations were significantly underrepresented in sporadic cases. All TSC1 mutations were predicted to be truncating, consistent with a structural or adaptor role for the encoded protein. In contrast, 22 patients had TSC2 missense mutations that were found predominantly in the GAP-related domain (8 cases) and in a small region encoded in exons 16 and 17, between nucleotides 1849 and 1859 (8 cases), consistent with the presence of residues performing key functions at these sites. Intellectual disability was significantly more frequent in tuberous sclerosis-2 sporadic cases than in tuberous sclerosis-1 sporadic cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10205261" 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="#65" class="mim-tip-reference" title="Young, J. M., Burley, M. W., Jeremiah, S. J., Jeganathan, D., Ekong, R., Osborne, J. P., Povey, S. <strong>A mutation screen of the TSC1 gene reveals 26 protein truncating mutations and 1 splice site mutation in a panel of 79 tuberous sclerosis patients.</strong> Ann. Hum. Genet. 62: 203-213, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9803264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9803264</a>] [<a href="https://doi.org/10.1046/j.1469-1809.1998.6230203.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9803264">Young et al. (1998)</a> performed a mutation screen of the TSC1 gene in a panel of 79 tuberous sclerosis patients. Twelve of the patients were from families showing linkage to 9q34 markers. Causative mutations in the TSC1 gene were found in 27 of these patients, and 5 other variations in the gene were identified. Twenty-six of the mutations were predicted to cause premature termination of the protein product of the gene and one mutation was in a splice site. The mutation screen showed that TSC1 mutations are rarer in sporadic tuberous sclerosis patients than in familial cases. This is consistent with the expectation that a larger proportion of the tuberous sclerosis-2 patients will be sporadic because of the more severe nature of TSC2 as compared to TSC1. <a href="#65" class="mim-tip-reference" title="Young, J. M., Burley, M. W., Jeremiah, S. J., Jeganathan, D., Ekong, R., Osborne, J. P., Povey, S. <strong>A mutation screen of the TSC1 gene reveals 26 protein truncating mutations and 1 splice site mutation in a panel of 79 tuberous sclerosis patients.</strong> Ann. Hum. Genet. 62: 203-213, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9803264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9803264</a>] [<a href="https://doi.org/10.1046/j.1469-1809.1998.6230203.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9803264">Young et al. (1998)</a> found that in family 214 of <a href="#50" class="mim-tip-reference" title="Povey, S., Burley, M. W., Attwood, J., Benham, F., Hunt, D., Jeremiah, S. J., Franklin, D., Gillett, G., Malas, S., Robson, E. B., Tippett, P., Edwards, J. H., Kwiatkowski, D. J., Super, M., Mueller, R., Fryer, A., Clarke, A., Webb, D., Osborne, J. <strong>Two loci for tuberous sclerosis: one on 9q34 and one on 16p13.</strong> Ann. Hum. Genet. 58: 107-127, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7979156/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7979156</a>] [<a href="https://doi.org/10.1111/j.1469-1809.1994.tb01881.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7979156">Povey et al. (1994)</a> a presumably nonpenetrant mother of a severely affected boy in one branch of the family did not carry the nonsense mutation leu250-to-ter present in affected individuals in other branches of the family. Furthermore, the grandmother of the severely affected boy was the 'connecting link' to the rest of the family not carrying the mutation, thus leading to the conclusion that the single ungual fibroma that had been thought to mean that she was affected was not in fact diagnostic of tuberous sclerosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9803264+7979156" 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="#3" class="mim-tip-reference" title="Ali, J. B. M., Sepp, T., Ward, S., Green, A. J., Yates, J. R. W. <strong>Mutations in the TSC1 gene account for a minority of patients with tuberous sclerosis.</strong> J. Med. Genet. 35: 969-972, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9863590/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9863590</a>] [<a href="https://doi.org/10.1136/jmg.35.12.969" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9863590">Ali et al. (1998)</a> screened 83 unrelated individuals with tuberous sclerosis for mutations in TSC1. Mutations were found in 16 of the 83 cases (19%). The mutations comprised base substitutions, small insertions, or small deletions giving rise to 6 nonsense mutations, 8 frameshifts, and 2 splice site mutations, all of which would be expected to result in a truncated or absent protein. In 8 of 10 cases showing linkage to the TSC1 locus, mutations were found. In the remaining 73 unassigned cases, only 8 mutations were found (11%). From these data, <a href="#3" class="mim-tip-reference" title="Ali, J. B. M., Sepp, T., Ward, S., Green, A. J., Yates, J. R. W. <strong>Mutations in the TSC1 gene account for a minority of patients with tuberous sclerosis.</strong> J. Med. Genet. 35: 969-972, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9863590/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9863590</a>] [<a href="https://doi.org/10.1136/jmg.35.12.969" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9863590">Ali et al. (1998)</a> estimated that TSC1 mutations account for 22% of tuberous sclerosis cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9863590" 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="#40" class="mim-tip-reference" title="Mayer, K., Ballhausen, W., Rott, H.-D. <strong>Mutation screening of the entire coding regions of the TSC1 and the TSC2 gene with the protein truncation test (PTT) identifies frequent splicing defects.</strong> Hum. Mutat. 14: 401-411, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10533066/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10533066</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(199911)14:5<401::AID-HUMU6>3.0.CO;2-R" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10533066">Mayer et al. (1999)</a> pointed out that all known TSC1 mutations, as well as most TSC2 mutations, truncate the proteins hamartin and tuberin, respectively. <a href="#40" class="mim-tip-reference" title="Mayer, K., Ballhausen, W., Rott, H.-D. <strong>Mutation screening of the entire coding regions of the TSC1 and the TSC2 gene with the protein truncation test (PTT) identifies frequent splicing defects.</strong> Hum. Mutat. 14: 401-411, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10533066/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10533066</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(199911)14:5<401::AID-HUMU6>3.0.CO;2-R" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10533066">Mayer et al. (1999)</a> described an RNA-based screening of the entire coding regions of both TSC genes for truncating mutations, applying the protein truncation test (PTT). Simultaneous investigation of both TSC genes in a group of 48 unassigned TSC patients, which were previously tested to exclude large intragenic TSC2 rearrangements, revealed aberrant migrating polypeptides resulting from truncating mutations in 9 TSC1 cases and in 16 TSC2 cases, while 3 TSC2 cases showed enlarged proteins. TSC1 mutations included 2 nonsense mutations, 4 insertions, and 3 splice mutations. Nineteen mutations identified in TSC2 comprised 4 different nonsense mutations in 5 patients, 1 deletion, 1 insertion, and 7 different splicing aberrations due to at least 8 different mutations found in 12 patients. Additional predicted truncating mutations according to PTT without possible identification of the causative alteration allowed assignment to TSC1 in 1 and TSC2 in 7 cases. Twelve patients without abnormalities in the PTT were assumed to harbor missense mutations, probably in TSC2. The high proportion of TSC2 splicing aberrations strengthens the importance of intronic disease-causing mutations and the application of RNA-based screening methods to confirm their consequences. <a href="#7" class="mim-tip-reference" title="Benit, P., Kara-Mostefa, A., Hadj-Rabia, S., Munnich, A., Bonnefont, J.-P. <strong>Protein truncation test for screening hamartin gene mutations and report of new disease-causing mutations.</strong> Hum. Mutat. 14: 428-432, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10533069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10533069</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(199911)14:5<428::AID-HUMU9>3.0.CO;2-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10533069">Benit et al. (1999)</a> likewise devised a protein truncation test to analyze the full-length coding sequence of TSC1. In a study of 15 cases (12 sporadic and 3 familial) by a combination of PTT and SSCP, they found 5 of 15 mutations, whereas PTT alone detected 4 of 15 truncating mutations, 2 of which escaped SSCP analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10533069+10533066" 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="#45" class="mim-tip-reference" title="Niida, Y., Lawrence-Smith, N., Banwell, A., Hammer, E., Lewis, J., Beauchamp, R. L., Sims, K., Ramesh, V., Ozelius, L. <strong>Analysis of both TSC1 and TSC2 for germline mutations in 126 unrelated patients with tuberous sclerosis.</strong> Hum. Mutat. 14: 412-422, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10533067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10533067</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(199911)14:5<412::AID-HUMU7>3.0.CO;2-K" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10533067">Niida et al. (1999)</a> reported mutation analysis of the entire coding region of the TSC1 and TSC2 genes in 126 unrelated TSC patients, including 40 familial and 86 sporadic cases, by SSCP followed by direct sequencing. Mutations were identified in a total of 74 (59%) cases, including 16 TSC1 mutations (5 sporadic and 11 familial) and 58 TSC2 mutations (42 sporadic and 16 familial). Overall, significantly more TSC2 mutations were found in this population, with a relatively equal distribution of mutations between TSC1 and TSC2 among the familial cases, but a marked underrepresentation of TSC1 mutations among the sporadic cases (p = 0.0035, Fisher exact test). All TSC1 mutations were predicted to be protein truncating; however, in TSC2 13 missense mutations were found, 5 clustering in the GAP-related domain and 3 others occurring in exon 16. Upon comparison of clinical manifestations, including the incidence of intellectual disability, they could not find any observable differences between TSC1 and TSC2 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10533067" 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="#12" class="mim-tip-reference" title="Carbonara, C., Longa, L., Grosso, E., Mazzucco, G., Borrone, C., Garre, M. L., Brisigotti, M., Filippi, G., Scabar, A., Giannotti, A., Falzoni, P., Monga, G., Garini, G., Gabrielli, M., Riegler, P., Danesino, C., Ruggieri, M., Magro, G., Migone, N. <strong>Apparent preferential loss of heterozygosity at TSC2 over TSC1 chromosomal region in tuberous sclerosis hamartomas.</strong> Genes Chromosomes Cancer 15: 18-25, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8824721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8824721</a>] [<a href="https://doi.org/10.1002/(SICI)1098-2264(199601)15:1<18::AID-GCC3>3.0.CO;2-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8824721">Carbonara et al. (1996)</a> studied LOH in both the TSC1 and TSC2 loci and 7 tumor suppressor gene-containing regions, p53 (<a href="/entry/191170">191170</a>), NF1 (<a href="/entry/613113">613113</a>), NF2 (<a href="/entry/607379">607379</a>), BRCA1 (<a href="/entry/113705">113705</a>), APC (<a href="/entry/611731">611731</a>), VHL (<a href="/entry/608537">608537</a>), and MLM (<a href="/entry/155600">155600</a>), in 20 hamartomas from 18 tuberous sclerosis patients. Overall, 8 angiomyolipomas, 8 giant cell astrocytomas, 1 cortical tuber, and 3 rhabdomyomas were analyzed. LOH at either TSC locus was found in a large fraction of the informative patients, both sporadic (7/14) and familial (1/4). A statistically significant preponderance of LOH of TSC2 was observed in the sporadic group (P less than 0.01). <a href="#12" class="mim-tip-reference" title="Carbonara, C., Longa, L., Grosso, E., Mazzucco, G., Borrone, C., Garre, M. L., Brisigotti, M., Filippi, G., Scabar, A., Giannotti, A., Falzoni, P., Monga, G., Garini, G., Gabrielli, M., Riegler, P., Danesino, C., Ruggieri, M., Magro, G., Migone, N. <strong>Apparent preferential loss of heterozygosity at TSC2 over TSC1 chromosomal region in tuberous sclerosis hamartomas.</strong> Genes Chromosomes Cancer 15: 18-25, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8824721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8824721</a>] [<a href="https://doi.org/10.1002/(SICI)1098-2264(199601)15:1<18::AID-GCC3>3.0.CO;2-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8824721">Carbonara et al. (1996)</a> suspected that bias in the selection for TSC patients with the most severe organ impairment was responsible for the finding. According to this suggestion, a TSC2 defect may confer a greater risk for early kidney failure or possibly a more rapid growth of a giant cell astrocytoma. None of the 7 antioncogenes tested showed LOH, indicating that the loss of either TSC gene product may be sufficient to promote hamartomatous cell growth. The observation of LOH at different markers in an astrocytoma and in an angiomyolipoma from the same patients suggested to the authors the multifocal origin of a second-hit mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8824721" 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="#62" class="mim-tip-reference" title="van Slegtenhorst, M., Verhoef, S., Tempelaars, A., Bakker, L., Wang, Q., Wessels, M., Bakker, R., Nellist, M., Lindhout, D., Halley, D., van den Ouweland, A. <strong>Mutational spectrum of the TSC1 gene in a cohort of 225 tuberous sclerosis complex patients: no evidence for genotype-phenotype correlation.</strong> J. Med. Genet. 36: 285-289, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10227394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10227394</a>]" pmid="10227394">Van Slegtenhorst et al. (1999)</a> reported mutation analysis of the TSC1 gene in a cohort of 225 unrelated patients. Of 29 mutations detected, all were small changes leading to a truncated protein except for a splice site mutation and 2 in-frame deletions in exons 7 and 15. No clear difference was observed in the clinical phenotype of patients with an in-frame deletion or a frameshift or nonsense mutation. <a href="#62" class="mim-tip-reference" title="van Slegtenhorst, M., Verhoef, S., Tempelaars, A., Bakker, L., Wang, Q., Wessels, M., Bakker, R., Nellist, M., Lindhout, D., Halley, D., van den Ouweland, A. <strong>Mutational spectrum of the TSC1 gene in a cohort of 225 tuberous sclerosis complex patients: no evidence for genotype-phenotype correlation.</strong> J. Med. Genet. 36: 285-289, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10227394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10227394</a>]" pmid="10227394">Van Slegtenhorst et al. (1999)</a> found no obvious underrepresentation of mutations among sporadic cases, in contrast to the findings of <a href="#31" class="mim-tip-reference" title="Jones, A. C., Shyamsundar, M. M., Thomas, M. W., Maynard, J., Idziaszczyk, S., Tomkins, S., Sampson, J. R., Cheadle, J. P. <strong>Comprehensive mutation analysis of TSC1 and TSC2--and phenotypic correlations in 150 families with tuberous sclerosis.</strong> Am. J. Hum. Genet. 64: 1305-1315, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10205261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10205261</a>] [<a href="https://doi.org/10.1086/302381" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10205261">Jones et al. (1999)</a>. <a href="#62" class="mim-tip-reference" title="van Slegtenhorst, M., Verhoef, S., Tempelaars, A., Bakker, L., Wang, Q., Wessels, M., Bakker, R., Nellist, M., Lindhout, D., Halley, D., van den Ouweland, A. <strong>Mutational spectrum of the TSC1 gene in a cohort of 225 tuberous sclerosis complex patients: no evidence for genotype-phenotype correlation.</strong> J. Med. Genet. 36: 285-289, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10227394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10227394</a>]" pmid="10227394">Van Slegtenhorst et al. (1999)</a> found no genotype-phenotype correlation for patients with TSC1 mutations compared to the overall population of tuberous sclerosis patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10205261+10227394" 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="#64" class="mim-tip-reference" title="Yamashita, Y., Ono, J., Okada, S., Wataya-Kaneda, M., Yoshikawa, K., Nishizawa, M., Hirayama, Y., Kobayashi, E., Seyama, K., Hino, O. <strong>Analysis of all exons of TSC1 and TSC2 genes for germline mutations in Japanese patients with tuberous sclerosis: report of 10 mutations.</strong> Am. J. Med. Genet. 90: 123-126, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10607950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10607950</a>]" pmid="10607950">Yamashita et al. (2000)</a> examined 27 unrelated Japanese patients with tuberous sclerosis for mutations in the TSC1 and TSC2 genes, using SSCP analysis of genomic DNA. They identified 4 mutations in TSC1 that they considered to be pathogenic, including 3 frameshifts and 1 nonsense mutation. All were expected to result in a truncated hamartin gene product. The authors found no difference in the risk for mental retardation between their series of tuberous sclerosis-1 and tuberous sclerosis-2 patients. In addition, the extent of protein truncation expected from the mutations did not correlate with the severity of clinical symptoms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10607950" 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="#11" class="mim-tip-reference" title="Carbonara, C., Longa, L., Grosso, E., Borrone, C., Garre, M. G., Brisigotti, M., Migone, N. <strong>9q34 loss of heterozygosity in a tuberous sclerosis astrocytoma suggests a growth suppressor-like activity also for the TSC1 gene.</strong> Hum. Molec. Genet. 3: 1829-1832, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849708</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849708">Carbonara et al. (1994)</a> presented evidence of loss of heterozygosity (LOH) at the tuberous sclerosis-1 critical region in a giant cell astrocytoma occurring in a patient with familial tuberous sclerosis. Segregation analysis showed that the 9q34 haplotype lost in the tumor carried the putative normal TSC1 gene. These data supported the hypothesis of both a germline and somatic loss-of-function mutation necessary for the development of tuberous sclerosis hamartomas and suggested a tumor-suppressor activity for the TSC1 gene product. (In the same astrocytoma, a second small region of LOH was found at 9p21.) <a href="#21" class="mim-tip-reference" title="Green, A. J., Johnson, P. H., Yates, J. R. W. <strong>The tuberous sclerosis gene on chromosome 9q34 acts as a growth suppressor.</strong> Hum. Molec. Genet. 3: 1833-1834, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849709/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849709</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1833" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849709">Green et al. (1994)</a> likewise found allele loss consistent with a tumor-suppressor role of the TSC1 gene. They studied 6 hamartomas from 4 sporadic and 2 familial cases of tuberous sclerosis, none of which showed allele loss for markers on 16p13.3. The hamartomas were paraffin-embedded sections of 3 renal angiomyolipomas, 2 giant cell astrocytomas, and a cardiac rhabdomyoma. One angiomyolipoma showed allele loss for the markers ABO, DBH, and D9S66. The family structure did not permit determination of the phase of the disease and marker alleles. Findings supported the assignment of tuberous sclerosis-1 to 9q34 and placed the gene between D9S149 and D9S67. Similar evidence had supported a growth suppressor role for the TSC2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7849709+7849708" 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="#22" class="mim-tip-reference" title="Green, A. J., Sepp, T., Yates, J. R. W. <strong>Clonality of tuberous sclerosis hamartomas shown by non-random X-chromosome inactivation.</strong> Hum. Genet. 97: 240-243, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8566961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8566961</a>] [<a href="https://doi.org/10.1007/BF02265273" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8566961">Green et al. (1996)</a> used nonrandom X chromosome inactivation studies to demonstrate the clonality of tuberous sclerosis hamartomas. Previously, LOH for DNA markers in the region of either the TSC1 gene on 9q34 or the TSC2 gene on 16p13.3 had supported the conclusion that these lesions are indeed clonal. In the studies of X-chromosome inactivation, <a href="#22" class="mim-tip-reference" title="Green, A. J., Sepp, T., Yates, J. R. W. <strong>Clonality of tuberous sclerosis hamartomas shown by non-random X-chromosome inactivation.</strong> Hum. Genet. 97: 240-243, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8566961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8566961</a>] [<a href="https://doi.org/10.1007/BF02265273" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8566961">Green et al. (1996)</a> examined clonality in 13 TSC hamartomas from female cases by analyzing X-chromosome inactivation in DNA extracted from archival paraffin-embedded tumors compared with normal tissue from the same patient. Seven of the cases were sporadic; 2 were from families linked to 9q34, 1 was from a family linked to 16p13.3 and 3 were from families too small to assign by linkage. Only 4 of the 13 hamartomas had previously shown LOH, 1 in the region of the TSC1 gene and 3 in the region of the TSC2 gene. A PCR assay was used to analyze differential methylation of the HpaII restriction site adjacent to the androgen-receptor triplet-repeat polymorphism on Xq11-q12. In 12 of the lesions, there was a skewed inactivation pattern, one X-chromosome being fully methylated and the other unmethylated. Normal tissue showed a random pattern of inactivation. The finding was considered particularly intriguing by the authors since the lesions were composed of more than 1 cell type. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8566961" 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="#25" class="mim-tip-reference" title="Henske, E. P., Scheithauer, B. W., Short, M. P., Wollmann, R., Nahmias, J., Hornigold, N., van Slegtenhorst, M., Welsh, C. T., Kwiatkowski, D. J. <strong>Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions.</strong> Am. J. Hum. Genet. 59: 400-406, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8755927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8755927</a>]" pmid="8755927">Henske et al. (1996)</a> analyzed 87 lesions from 47 TSC patients for LOH in the TSC1 and TSC2 regions. Of the 28 patients with angiomyolipomas or rhabdomyomas, LOH for 16p13 was detected in lesions from 12 (57%). LOH for 9q34 was detected in only 1 patient. The authors noted that LOH occurred in only 4% of TSC brain lesions and suggested that TSC brain lesions may result from a different pathogenetic mechanism than TSC kidney or rhabdomyoma lesions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8755927" 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="#46" class="mim-tip-reference" title="Niida, Y., Stemmer-Rachamimov, A. O., Logrip, M., Tapon, D., Perez, R., Kwiatkowski, D. J., Sims, K., MacCollin, M., Louis, D. N., Ramesh, V. <strong>Survey of somatic mutations in tuberous sclerosis complex (TSC) hamartomas suggests different genetic mechanisms for pathogenesis of TSC lesions.</strong> Am. J. Hum. Genet. 69: 493-503, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11468687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11468687</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11468687[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/10.1086/321972" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11468687">Niida et al. (2001)</a> analyzed 24 hamartomas from 10 patients for second-hit mutations by multiple methods including LOH analysis, SSCP screening of TSC1 and TSC2, promoter methylation studies of TSC2, and clonality analysis. The results provided evidence that complete inactivation of the TSC genes is characteristic of renal angiomyolipomas but not of other TSC lesions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11468687" 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="#54" class="mim-tip-reference" title="Sepp, T., Yates, J. R. W., Green, A. J. <strong>Loss of heterozygosity in tuberous sclerosis hamartomas.</strong> J. Med. Genet. 33: 962-964, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8950679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8950679</a>] [<a href="https://doi.org/10.1136/jmg.33.11.962" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8950679">Sepp et al. (1996)</a> described the spectrum of LOH in 51 hamartomas from 34 cases of tuberous sclerosis. Of 51 hamartomas analyzed, 21 (41%) showed LOH; 16 hamartomas showed LOH around TSC2 and 5 showed LOH in the vicinity of TSC1. No hamartomas showed LOH for markers around both loci. <a href="#54" class="mim-tip-reference" title="Sepp, T., Yates, J. R. W., Green, A. J. <strong>Loss of heterozygosity in tuberous sclerosis hamartomas.</strong> J. Med. Genet. 33: 962-964, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8950679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8950679</a>] [<a href="https://doi.org/10.1136/jmg.33.11.962" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8950679">Sepp et al. (1996)</a> reported that there did not appear to be any major differences in the frequency of LOH between the different types of hamartoma. LOH was observed in 7 of 17 angiomyolipomas, 5 of 9 giant cell astrocytomas, 3 of 8 fibromas, 3 of 5 cortical tubers, and in a shagreen patch, a cardiac rhabdomyoma, and a renal carcinoma. <a href="#54" class="mim-tip-reference" title="Sepp, T., Yates, J. R. W., Green, A. J. <strong>Loss of heterozygosity in tuberous sclerosis hamartomas.</strong> J. Med. Genet. 33: 962-964, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8950679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8950679</a>] [<a href="https://doi.org/10.1136/jmg.33.11.962" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8950679">Sepp et al. (1996)</a> noted that the excess of LOH for the TSC2 region on chromosome 16p13.3 may simply reflect that the TSC1 locus is less well defined and that LOH for 9q34 is therefore harder to find. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8950679" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Bjornsson, J., Short, M. P., Kwiatkowski, D. J., Henske, E. P. <strong>Tuberous sclerosis-associated renal cell carcinoma.</strong> Am. J. Path. 149: 1201-1208, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8863669/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8863669</a>]" pmid="8863669">Bjornsson et al. (1996)</a> studied 6 TSC-associated RCCs. Their findings suggested that some TSC-associated RCCs have clinical, pathologic, and genetic features which distinguish them from sporadic RCC. Clinically the TSC-associated RCC occurred at a younger age (36 years) than sporadic tumors and occurred primarily in women (5 of 6 cases). <a href="#9" class="mim-tip-reference" title="Bjornsson, J., Short, M. P., Kwiatkowski, D. J., Henske, E. P. <strong>Tuberous sclerosis-associated renal cell carcinoma.</strong> Am. J. Path. 149: 1201-1208, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8863669/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8863669</a>]" pmid="8863669">Bjornsson et al. (1996)</a> reported that 5 tumors displayed clear cell morphology and 2 of those 5 had high-grade spindle cell areas in addition to granular cell histology. Of the 6 patients studied, 4 died from their carcinoma and 3 had pulmonary metastases in addition to retroperitoneal spread. The 2 surviving patients had tumors that were detected incidentally (one at surgery for angiomyolipoma and renal hemorrhage, the other at surgery for renal cysts). Immunostaining for a melanocyte-associated marker, HMB-45, was positive in 4 of the 6 cases. LOH was observed on 9q34, 16p13.3, and in 2 cases on chromosome 3p. <a href="#9" class="mim-tip-reference" title="Bjornsson, J., Short, M. P., Kwiatkowski, D. J., Henske, E. P. <strong>Tuberous sclerosis-associated renal cell carcinoma.</strong> Am. J. Path. 149: 1201-1208, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8863669/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8863669</a>]" pmid="8863669">Bjornsson et al. (1996)</a> noted that the tumor with LOH of 9q34 alone was incidentally detected and lacked anaplastic features. In contrast, the tumors with LOH on 9q34 and 3p had anaplastic features and metastasized. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8863669" 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="#14" class="mim-tip-reference" title="Cheadle, J. P., Reeve, M. P., Sampson, J. R., Kwiatkowski, D. J. <strong>Molecular genetic advances in tuberous sclerosis.</strong> Hum. Genet. 107: 97-114, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11030407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11030407</a>] [<a href="https://doi.org/10.1007/s004390000348" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11030407">Cheadle et al. (2000)</a> reviewed the molecular genetic advances in tuberous sclerosis. They found reports of 154 cases with mutations in the TSC1 gene and 292 cases with mutations in the TSC2 gene. Forty-seven percent (73/154) of TSC1 mutations were single-base substitutions, 82% of which were nonsense mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11030407" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of 224 index patients with tuberous sclerosis, <a href="#16" class="mim-tip-reference" title="Dabora, S. L., Jozwiak, S., Franz, D. N., Roberts, P. S., Nieto, A., Chung, J., Choy, Y.-S., Reeve, M. P., Thiele, E., Egelhoff, J. C., Kasprzyk-Obara, J., Domanska-Pakiela, D., Kwiatkowski, D. J. <strong>Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs.</strong> Am. J. Hum. Genet. 68: 64-80, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11112665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11112665</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11112665[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/10.1086/316951" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11112665">Dabora et al. (2001)</a> found mutations in 186 (83%), comprising 138 small TSC2 mutations, 20 large TSC2 mutations, and 28 small TSC1 mutations. Clinical assessment indicated that sporadic patients with TSC1 mutations had, on average, milder disease than did patients with TSC2 mutations, despite being of similar age. They had a lower frequency of seizures and moderate to severe mental retardation, fewer subependymal nodules and cortical tubers, less severe kidney involvement, no retinal hamartomas, and less severe facial angiofibroma. Patients in whom no mutation was found also had disease that was milder, on average, than that in patients with TSC2 mutations. Although there was overlap in the spectrum of many clinical features of patients with TSC1 versus TSC2 mutations, some features (grade 2-4 kidney cysts or angiomyolipomas, forehead plaques, retinal hamartomas, and liver angiomyolipomas) were very rare or not seen at all in TSC1 patients. Thus, both germline and somatic mutations appear to be less common in TSC1 than in TSC2. The reduced severity of disease in patients without defined mutations suggests that many of these patients are mosaic for a TSC2 mutation and/or have TSC because of mutations in an as yet undefined locus with a relatively mild clinical phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11112665" 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="#38" class="mim-tip-reference" title="Langkau, N., Martin, N., Brandt, R., Zugge, K., Quast, S., Wiegele, G., Jauch, A., Rehm, M., Kuhl, A., Mack-Vetter, M., Zimmerhackl, L. B., Janssen, B. <strong>TSC1 and TSC2 mutations in tuberous sclerosis, the associated phenotypes and a model to explain observed TSC1/TSC2 frequency ratios.</strong> Europ. J. Pediat. 161: 393-402, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12111193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12111193</a>] [<a href="https://doi.org/10.1007/s00431-001-0903-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12111193">Langkau et al. (2002)</a> genotyped 68 unrelated and nonselected patients (59 sporadic and 9 familial) with clinically confirmed TSC and identified 29 mutations in the TSC2 gene and 2 mutations in the TSC1 gene. They noted that the TSC1-TSC2 mutation ratio in this group of patients differed significantly from the 1:1 ratio previously predicted on the basis of linkage studies. They suggested that milder phenotypes are more often associated with TSC1 mutations and are likely to escape ascertainment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12111193" 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>Many mRNAs carrying mutations that encode a truncated protein are subject to nonsense-mediated mRNA decay (NMD), which results in reduced levels of mutant transcript. Virtually all TSC1 mutations truncate the protein product. <a href="#29" class="mim-tip-reference" title="Jeganathan, D., Fox, M. F., Young, J. M., Yates, J. R. W., Osborne, J. P., Povey, S. <strong>Nonsense-mediated RNA decay in the TSC1 gene suggests a useful tool pre- and post-positional cloning.</strong> Hum. Genet. 111: 555-565, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12436247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12436247</a>] [<a href="https://doi.org/10.1007/s00439-002-0821-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12436247">Jeganathan et al. (2002)</a> used coding and 3-prime untranslated region polymorphisms in TSC1 to develop a transcript imbalance assay to investigate TSC1 transcript levels in patients. This approach allowed the correct identification of 6 of 7 TSC1 patients tested blind from a panel of TSC1 and TSC2 patients, with no false positives. The extent of NMD in TSC1 correlated with each individual mutation regardless of intrafamilial variation in clinical features and with no strong evidence for positional bias. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12436247" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Au, K. S., Williams, A. T., Roach, E. S., Batchelor, L., Sparagana, S. P., Delgado, M. R., Wheless, J. W., Baumgartner, J. E., Roa, B. B., Wilson, C. M., Smith-Knuppel, T. K., Cheung, M.-Y. C., Whittemore, V. H., King, T. M., Northrup, H. <strong>Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States.</strong> Genet. Med. 9: 88-100, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17304050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17304050</a>] [<a href="https://doi.org/10.1097/gim.0b013e31803068c7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17304050">Au et al. (2007)</a> performed mutational analyses on 325 individuals with definite tuberous sclerosis complex diagnostic status. The authors identified mutations in 72% (199 of 257) of de novo and 77% (53 of 68) of familial cases, with 17% of mutations in the TSC1 gene and 50% in the TSC2 gene. There were 4% unclassified variants and 29% with no mutation identified. Genotype/phenotype analyses of all observed tuberous sclerosis complex findings in probands were performed, including several clinical features not analyzed in 2 previous large studies (see, e.g., <a href="#52" class="mim-tip-reference" title="Sancak, O., Nellist, M., Goedbloed, M., Elfferich, P., Wouters, C., Maat-Kievit, A., Zonnenberg, B., Verhoef, S., Halley, D., van den Ouweland, A. <strong>Mutational analysis of the TSC1 and TSC2 genes in a diagnostic setting: genotype-phenotype correlations and comparison of diagnostic DNA techniques in tuberous sclerosis complex.</strong> Europ. J. Hum. Genet. 13: 731-741, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15798777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15798777</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15798777">Sancak et al., 2005</a>). <a href="#5" class="mim-tip-reference" title="Au, K. S., Williams, A. T., Roach, E. S., Batchelor, L., Sparagana, S. P., Delgado, M. R., Wheless, J. W., Baumgartner, J. E., Roa, B. B., Wilson, C. M., Smith-Knuppel, T. K., Cheung, M.-Y. C., Whittemore, V. H., King, T. M., Northrup, H. <strong>Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States.</strong> Genet. Med. 9: 88-100, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17304050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17304050</a>] [<a href="https://doi.org/10.1097/gim.0b013e31803068c7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17304050">Au et al. (2007)</a> showed that patients with TSC2 mutations have significantly more hypomelanotic macules and learning disability in contrast to those with TSC1 mutations, findings not noted in previous studies. The authors also observed results consistent with 2 similar studies suggesting that individuals with mutations in TSC2 have more severe symptoms. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15798777+17304050" 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="#44" class="mim-tip-reference" title="Nellist, M., van den Heuvel, D., Schluep, D., Exalto, C., Goedbloed, M., Maat-Kievit, A., van Essen, T., van Spaendonck-Zwarts, K., Jansen, F., Helderman, P., Bartalini, G., Vierimaa, O., Penttinen, M., van den Ende, J., van den Ouweland, A., Halley, D. <strong>Missense mutations to the TSC1 gene cause tuberous sclerosis complex.</strong> Europ. J. Hum. Genet. 17: 319-328, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18830229/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18830229</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18830229[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/ejhg.2008.170" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18830229">Nellist et al. (2009)</a> identified 8 different missense mutations in the TSC1 gene (see, e.g., M224R; <a href="#0008">605284.0008</a> and L180P; <a href="#0009">605284.0009</a>) that segregated with tuberous sclerosis. In vitro functional expression studies demonstrated that these changes resulted in reduced levels of TSC1 and a reduction in TSC1-dependent inhibition of mTOR activity, as detected by immunoblotting. In each case, the functional characterization was consistent with the genetic and phenotypic findings, indicating that the missense changes were pathogenic. <a href="#44" class="mim-tip-reference" title="Nellist, M., van den Heuvel, D., Schluep, D., Exalto, C., Goedbloed, M., Maat-Kievit, A., van Essen, T., van Spaendonck-Zwarts, K., Jansen, F., Helderman, P., Bartalini, G., Vierimaa, O., Penttinen, M., van den Ende, J., van den Ouweland, A., Halley, D. <strong>Missense mutations to the TSC1 gene cause tuberous sclerosis complex.</strong> Europ. J. Hum. Genet. 17: 319-328, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18830229/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18830229</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18830229[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/ejhg.2008.170" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18830229">Nellist et al. (2009)</a> concluded that mutations close to the N terminus of TSC1 (amino acids 117 to 224) reduce the steady-state levels of TSC1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18830229" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Pulmonary Lymphangioleiomyomatosis</em></strong></p><p>
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Pulmonary lymphangioleiomyomatosis (LAM; <a href="/entry/606690">606690</a>) is a destructive lung disease characterized by a diffuse hamartomatous proliferation of smooth muscle cells in the lungs. Pulmonary LAM can occur as an isolated form (sporadic LAM) or in association with tuberous sclerosis complex (TSC-LAM). <a href="#53" class="mim-tip-reference" title="Sato, T., Seyama, K., Fujii, H., Maruyama, H., Setoguchi, Y., Iwakami, S., Fukuchi, Y., Hino, O. <strong>Mutation analysis of the TSC1 and TSC2 genes in Japanese patients with pulmonary lymphangioleiomyomatosis.</strong> J. Hum. Genet. 47: 20-28, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11829138/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11829138</a>] [<a href="https://doi.org/10.1007/s10038-002-8651-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11829138">Sato et al. (2002)</a> studied the TSC1 and TSC2 genes in 6 Japanese patients with TSC-LAM and 22 patients with sporadic LAM and identified 6 novel mutations. TSC2 germline mutations were detected in 2 (33.3%) of the 6 patients with TSC-LAM, and a TSC1 germline mutation was detected in 1 (4.5%) of the 22 sporadic LAM patients. In accordance with the tumor suppressor model, LOH was detected in LAM cells from 3 of 4 patients with TSC-LAM and from 4 of 8 patients with sporadic LAM. Furthermore, an identical LOH or 2 identical somatic mutations were demonstrated in LAM cells microdissected from several tissues, suggesting that LAM cells can spread from one lesion to another. These results confirmed the prevailing concept of pathogenesis of LAM: TSC-LAM has a germline mutation, but sporadic LAM does not; sporadic LAM is a TSC2 disease with 2 somatic mutations; and a variety of TSC mutations can cause LAM. However, this study indicated that a fraction of sporadic LAM can be a TSC1 disease; therefore, both TSC genes should be examined, even in patients with sporadic LAM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11829138" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Focal Cortical Dysplasia, Type II, Somatic</em></strong></p><p>
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Focal cortical dysplasia type II (FCORD2; <a href="/entry/607341">607341</a>) is characterized by a localized malformation of the neocortex and underlying white matter. Balloon cells, similar to those observed in TSC, are present in many cases, referred to by <a href="#6" class="mim-tip-reference" title="Becker, A. J., Urbach, H., Scheffler, B., Baden, T., Normann, S., Lahl, R., Pannek, H. W., Tuxhorn, I., Elger, C. E., Schramm, J., Wiestler, O. D., Blumcke, I. <strong>Focal cortical dysplasia of Taylor's balloon cell type: mutational analysis of the TSC1 gene indicates a pathogenic relationship to tuberous sclerosis.</strong> Ann. Neurol. 52: 29-37, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12112044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12112044</a>] [<a href="https://doi.org/10.1002/ana.10251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12112044">Becker et al. (2002)</a> as FCD(bc). <a href="#6" class="mim-tip-reference" title="Becker, A. J., Urbach, H., Scheffler, B., Baden, T., Normann, S., Lahl, R., Pannek, H. W., Tuxhorn, I., Elger, C. E., Schramm, J., Wiestler, O. D., Blumcke, I. <strong>Focal cortical dysplasia of Taylor's balloon cell type: mutational analysis of the TSC1 gene indicates a pathogenic relationship to tuberous sclerosis.</strong> Ann. Neurol. 52: 29-37, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12112044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12112044</a>] [<a href="https://doi.org/10.1002/ana.10251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12112044">Becker et al. (2002)</a> studied alterations of the TSC1 and TSC2 genes in a cohort of 48 patients with chronic, focal epilepsy and histologically documented FCD(bc). DNA was obtained after microdissection and laser-assisted isolation of balloon cells, dysplastic neurons, and nonlesional cells from adjacent normal brain tissue. Sequence alterations resulting in amino acid exchange of the TSC1 gene product affecting exons 5 and 17 and silent base exchanges in exons 14 and 22 were increased in patients with FCD(bc) compared with 200 controls. Sequence alterations were detected in FCD(bc) and adjacent normal cells. In 24 patients, DNA was suitable to study LOH at the TSC1 gene locus in microdissected FCD(bc) samples compared with control tissues. LOH was found in 11 FCD(bc) cases. In the TSC2 gene, only silent polymorphisms were detected at similar frequencies as in controls. <a href="#6" class="mim-tip-reference" title="Becker, A. J., Urbach, H., Scheffler, B., Baden, T., Normann, S., Lahl, R., Pannek, H. W., Tuxhorn, I., Elger, C. E., Schramm, J., Wiestler, O. D., Blumcke, I. <strong>Focal cortical dysplasia of Taylor's balloon cell type: mutational analysis of the TSC1 gene indicates a pathogenic relationship to tuberous sclerosis.</strong> Ann. Neurol. 52: 29-37, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12112044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12112044</a>] [<a href="https://doi.org/10.1002/ana.10251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12112044">Becker et al. (2002)</a> concluded that FCD(bc) constitutes a clinicopathologic entity with distinct neuroradiologic, neuropathologic, and molecular genetic features, and suggested the TSC1 gene has a role in its development, with a pathogenic relationship between it and the TSC complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12112044" 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="Becker, A. J., Urbach, H., Scheffler, B., Baden, T., Normann, S., Lahl, R., Pannek, H. W., Tuxhorn, I., Elger, C. E., Schramm, J., Wiestler, O. D., Blumcke, I. <strong>Focal cortical dysplasia of Taylor's balloon cell type: mutational analysis of the TSC1 gene indicates a pathogenic relationship to tuberous sclerosis.</strong> Ann. Neurol. 52: 29-37, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12112044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12112044</a>] [<a href="https://doi.org/10.1002/ana.10251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12112044">Becker et al. (2002)</a> noted that LOH for alleles at 16p13.3 (where the TSC2 gene is located) has been observed in brain lesions of TSC, and at 9q34 (where the TSC1 gene is located) in extracerebral lesions of TSC. Their findings of LOH related to the TSC1 gene in focal cortical dysplasia are possibly relevant to the 2-hit hypothesis for the inactivation of tumor suppressor genes. The observed combination of LOH within the TSC1 locus and sequence polymorphism in the other alleles suggests that the latter functions as a predisposing germline variant with low penetrance and a severely restricted manifestation pattern. Given that TSC1 and TSC2 may act as a cell cycle-regulating complex (<a href="#49" class="mim-tip-reference" title="Potter, C. J., Huang, H., Xu, T. <strong>Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size.</strong> Cell 105: 357-368, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11348592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11348592</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00333-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11348592">Potter et al., 2001</a>; <a href="#56" class="mim-tip-reference" title="Tapon, N., Ito, N., Dickson, B. J., Treisman, J. E., Hariharan, I. K. <strong>The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation.</strong> Cell 105: 345-355, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11348591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11348591</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00332-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11348591">Tapon et al., 2001</a>), such variant alleles may induce proliferation activity for a limited time during brain development. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11348592+11348591+12112044" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a detailed genotype-phenotype analysis of 33 patients with focal cortical dysplasia, including 23 with FCD type II, <a href="#23" class="mim-tip-reference" title="Gumbinger, C., Rohsbach, C. B., Schulze-Bonhage, A., Korinthenberg, R., Zentner, J., Haffner, M., Fauser, S. <strong>Focal cortical dysplasia: a genotype-phenotype analysis of polymorphisms and mutations in the TSC genes.</strong> Epilepsia 50: 1396-1408, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19175396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19175396</a>] [<a href="https://doi.org/10.1111/j.1528-1167.2008.01979.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19175396">Gumbinger et al. (2009)</a> identified several sequence variations in the TSC1 and TSC2 genes in both lesional brain tissue and blood of the patients, but in similar frequencies to that of the normal population. Most of the sequence alterations were silent. <a href="#23" class="mim-tip-reference" title="Gumbinger, C., Rohsbach, C. B., Schulze-Bonhage, A., Korinthenberg, R., Zentner, J., Haffner, M., Fauser, S. <strong>Focal cortical dysplasia: a genotype-phenotype analysis of polymorphisms and mutations in the TSC genes.</strong> Epilepsia 50: 1396-1408, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19175396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19175396</a>] [<a href="https://doi.org/10.1111/j.1528-1167.2008.01979.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19175396">Gumbinger et al. (2009)</a> concluded that focal cortical dysplasia is not caused by mutation in the TSC genes and does not appear to be promoted by TSC polymorphisms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19175396" 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 brain tissue resected from 4 unrelated children with seizures due to FCD type II (FCORD2; <a href="/entry/607341">607341</a>), including 3 with type IIa and 1 with type IIb, <a href="#39" class="mim-tip-reference" title="Lim, J. S., Gopalappa, R., Kim, S. H., Ramakrishna, S., Lee, M., Kim, W., Kim, J., Park, S. M., Lee, J., Oh, J.-H., Kim, H. D., Park, C.-H., Lee, J. S., Kim, S., Kim, D. S., Han, J. M., Kang, H.-C., Kim, H., Lee, J. H. <strong>Somatic mutations in TSC1 and TSC2 cause focal cortical dysplasia.</strong> Am. J. Hum. Genet. 100: 454-472, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28215400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28215400</a>] [<a href="https://doi.org/10.1016/j.ajhg.2017.01.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28215400">Lim et al. (2017)</a> identified de novo somatic missense mutations in the TSC1 gene (R22W, <a href="#0010">605284.0010</a> and R204C, <a href="#0011">605284.0011</a>). The mutations, which were found by targeted sequencing of genes in the MTOR pathway, showed very low frequency in brain tissue, less than 3%. The patients were part of a cohort of 40 individuals with FCD type II whose brain tissue was negative for somatic mTOR mutations. Patient dystrophic brain cells and TSC1 mutant-transfected cells showed increased S6K phosphorylation (RPS6KB1; <a href="/entry/608938">608938</a>) compared to wildtype, consistent with hyperactivation of the mTOR pathway. Mutant TSC1 also showed impaired binding to TSC2, indicating disruption of the TSC1-TSC2 complex. Abnormal S6K phosphorylation in transfected cells was inhibited by treatment with rapamycin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28215400" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Everolimus Sensitivity</em></strong></p><p>
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<a href="#28" class="mim-tip-reference" title="Iyer, G. Hanrahan, A. J., Milowsky, M. I., Al-Ahmadie, H., Scott, S. N., Janakiraman, M., Pirun, M., Sander, C., Socci, N. D., Ostrovnaya, I., Viale, A., Heguy, A., Peng, L., Chan, T. A., Bochner, B., Bajorin, D. F., Berger, M. F., Taylor, B. S., Solit, D. B. <strong>Genome sequencing identifies a basis for everolimus sensitivity.</strong> Science 338: 221 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22923433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22923433</a>] [<a href="https://doi.org/10.1126/science.1226344" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22923433">Iyer et al. (2012)</a> studied the tumor genome of a patient with metastatic bladder cancer who achieved a durable (greater than 2 years) and ongoing complete response to everolimus, a drug targeting the mTORC1 complex (see <a href="/entry/601231">601231</a>). <a href="#28" class="mim-tip-reference" title="Iyer, G. Hanrahan, A. J., Milowsky, M. I., Al-Ahmadie, H., Scott, S. N., Janakiraman, M., Pirun, M., Sander, C., Socci, N. D., Ostrovnaya, I., Viale, A., Heguy, A., Peng, L., Chan, T. A., Bochner, B., Bajorin, D. F., Berger, M. F., Taylor, B. S., Solit, D. B. <strong>Genome sequencing identifies a basis for everolimus sensitivity.</strong> Science 338: 221 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22923433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22923433</a>] [<a href="https://doi.org/10.1126/science.1226344" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22923433">Iyer et al. (2012)</a> identified a 2-bp deletion in the TSC1 gene resulting in a frameshift truncation, and a nonsense mutation in the NF2 (<a href="/entry/607379">607379</a>) gene. <a href="#28" class="mim-tip-reference" title="Iyer, G. Hanrahan, A. J., Milowsky, M. I., Al-Ahmadie, H., Scott, S. N., Janakiraman, M., Pirun, M., Sander, C., Socci, N. D., Ostrovnaya, I., Viale, A., Heguy, A., Peng, L., Chan, T. A., Bochner, B., Bajorin, D. F., Berger, M. F., Taylor, B. S., Solit, D. B. <strong>Genome sequencing identifies a basis for everolimus sensitivity.</strong> Science 338: 221 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22923433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22923433</a>] [<a href="https://doi.org/10.1126/science.1226344" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22923433">Iyer et al. (2012)</a> sequenced both genes in the second cohort of 96 high-grade bladder cancers and identified 5 additional somatic TSC1 mutations, whereas no additional NF2 mutations were detected. Subsequently, <a href="#28" class="mim-tip-reference" title="Iyer, G. Hanrahan, A. J., Milowsky, M. I., Al-Ahmadie, H., Scott, S. N., Janakiraman, M., Pirun, M., Sander, C., Socci, N. D., Ostrovnaya, I., Viale, A., Heguy, A., Peng, L., Chan, T. A., Bochner, B., Bajorin, D. F., Berger, M. F., Taylor, B. S., Solit, D. B. <strong>Genome sequencing identifies a basis for everolimus sensitivity.</strong> Science 338: 221 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22923433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22923433</a>] [<a href="https://doi.org/10.1126/science.1226344" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22923433">Iyer et al. (2012)</a> explored whether TSC1 mutations is a biomarker of clinical benefit from everolimus therapy in bladder cancer, and studied 13 additional bladder cancer patients treated with everolimus. Three additional tumors harbored nonsense mutations in TSC1, including 2 patients who had minor responses to everolimus (17 and 24% tumor regression, respectively). Tumors from 8 of the 9 patients who showed disease progression were TSC1 wildtype. Patients with TSC1-mutant tumors remained on everolimus longer than those with wildtype tumors (7.7 vs 2.0 months, p = 0.004) with a significant improvement in time to recurrence (4.1 vs 1.8 months; hazard ratio = 18.5, 95% confidence interval 2.1 to 162, p = 0.001). <a href="#28" class="mim-tip-reference" title="Iyer, G. Hanrahan, A. J., Milowsky, M. I., Al-Ahmadie, H., Scott, S. N., Janakiraman, M., Pirun, M., Sander, C., Socci, N. D., Ostrovnaya, I., Viale, A., Heguy, A., Peng, L., Chan, T. A., Bochner, B., Bajorin, D. F., Berger, M. F., Taylor, B. S., Solit, D. B. <strong>Genome sequencing identifies a basis for everolimus sensitivity.</strong> Science 338: 221 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22923433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22923433</a>] [<a href="https://doi.org/10.1126/science.1226344" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22923433">Iyer et al. (2012)</a> concluded that mTORC1-directed therapies may be most effective in cancer patients whose tumors harbor TSC1 somatic mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22923433" 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="#33" class="mim-tip-reference" title="Kobayashi, T., Minowa, O., Sugitani, Y., Takai, S., Mitani, H., Kobayashi, E., Noda, T., Hino, O. <strong>A germ-line Tsc1 mutation causes tumor development and embryonic lethality that are similar, but not identical to, those caused by Tsc2 mutation in mice.</strong> Proc. Nat. Acad. Sci. 98: 8762-8767, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11438694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11438694</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11438694[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.151033798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11438694">Kobayashi et al. (2001)</a> established a line of Tsc1 knockout mice by gene targeting. Heterozygous mutant mice (Tsc1 +/-) developed renal and extrarenal tumors such as hepatic hemangiomas. In these tumors, loss of the wildtype Tsc1 allele was observed. Homozygous Tsc1 mutants died around embryonic days 10.5 to 11.5, frequently associated with neural tube unclosure. As a whole, phenotypes of Tsc1-KO mice resembled those of Tsc2-KO mice previously reported, suggesting that the presumptive common pathway for the Tsc1 and Tsc2 products may exist in mice as is thought to be the case in humans. Notably, however, development of renal tumors in Tsc1 +/- mice was apparently slower than that in Tsc2 +/- mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11438694" 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="#36" class="mim-tip-reference" title="Kwiatkowski, D. J., Zhang, H., Bandura, J. L., Heiberger, K. M., Glogauer, M., el-Hashemite, N., Onda, H. <strong>A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells.</strong> Hum. Molec. Genet. 11: 525-534, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11875047/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11875047</a>] [<a href="https://doi.org/10.1093/hmg/11.5.525" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11875047">Kwiatkowski et al. (2002)</a> developed a murine model of TSC1 disease wherein the mutant allele lacked exons 17 and 18, which leads to premature termination. Tsc1-null embryos died at midgestation from a failure of liver development. Tsc1 heterozygotes developed kidney cystadenomas and liver hemangiomas at high frequency, but the incidence of kidney tumors was somewhat lower than in Tsc2 heterozygous mice. Liver hemangiomas were more common, more severe, and caused higher mortality in female than in male Tsc1 heterozygotes. Tsc1-null embryo fibroblast lines exhibited persistent phosphorylation of the p70-S6K and its substrate S6, which was sensitive to treatment with rapamycin, indicating constitutive activation of the MTOR-S6K pathway due to loss of the Tsc1 protein, hamartin. Hyperphosphorylation of S6 was also seen in kidney tumors in the heterozygous mice, suggesting that inhibition of this pathway may aid in control of TSC hamartomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11875047" 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="#58" class="mim-tip-reference" title="Uhlmann, E. J., Apicelli, A. J., Baldwin, R. L., Burke, S. P., Bajenaru, M. L., Onda, H., Kwiatkowski, D., Gutmann, D. H. <strong>Heterozygosity for the tuberous sclerosis complex (TSC) gene products results in increased astrocyte numbers and decreased p27-Kip1 expression in TSC2 +/- cells.</strong> Oncogene 21: 4050-4059, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12037687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12037687</a>] [<a href="https://doi.org/10.1038/sj.onc.1205435" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12037687">Uhlmann et al. (2002)</a> demonstrated that heterozygous Tsc1 and Tsc2 mice exhibit increased numbers of astrocytes, suggesting that hamartin and tuberin are important growth regulators for astrocytes. To study the consequence of hamartin loss on astrocyte function, <a href="#59" class="mim-tip-reference" title="Uhlmann, E. J., Wong, M., Baldwin, R. L., Bajenaru, M. L., Onda, H., Kwiatkowski, D. J., Yamada, K., Gutmann, D. H. <strong>Astrocyte-specific TSC1 conditional knockout mice exhibit abnormal neuronal organization and seizures.</strong> Ann. Neurol. 52: 285-296, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12205640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12205640</a>] [<a href="https://doi.org/10.1002/ana.10283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12205640">Uhlmann et al. (2002)</a> generated mice in which the Tsc1 gene was specifically inactivated in astrocytes. The mice demonstrated an age-dependent progression of increased astrocyte proliferation, abnormal neuronal organization in the hippocampus, seizures, and death. The findings suggested that the increase in astrocyte proliferation preceded the neuronal abnormalities, causing mass effect changes or disturbance of complex astrocyte-neuron interactions. In culture, the Tsc1-null astrocytes grew in association with reduced expression of the cell cycle regulator p27(KIP1) (<a href="/entry/600778">600778</a>), suggesting disruption of a TSC-mediated growth regulation complex involving p27(KIP1). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12037687+12205640" 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="#41" class="mim-tip-reference" title="Meikle, L., McMullen, J. R., Sherwood, M. C., Lader, A. S., Walker, V., Chan, J. A., Kwiatkowski, D. J. <strong>A mouse model of cardiac rhabdomyoma generated by loss of Tsc1 in ventricular myocytes.</strong> Hum. Molec. Genet. 14: 429-435, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15601645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15601645</a>] [<a href="https://doi.org/10.1093/hmg/ddi039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15601645">Meikle et al. (2005)</a> developed a conditional mouse mutant of Tsc1. Mice with ventricular loss of Tsc1 had a median survival of 6 months and developed a dilated cardiomyopathy with the occurrence of scattered foci of enlarged ventricular myocytes. The enlarged cells were PAS-positive, indicating the presence of excess glycogen, and expressed elevated levels of phospho-S6 (RPS6; <a href="/entry/180460">180460</a>), similar to findings in patient rhabdomyoma cells. The observations were consistent with a 2-hit mechanism for rhabdomyoma formation. However, the mice showed no evidence of fetal/neonatal demise, and there was no evidence of proliferation in the lesions. <a href="#41" class="mim-tip-reference" title="Meikle, L., McMullen, J. R., Sherwood, M. C., Lader, A. S., Walker, V., Chan, J. A., Kwiatkowski, D. J. <strong>A mouse model of cardiac rhabdomyoma generated by loss of Tsc1 in ventricular myocytes.</strong> Hum. Molec. Genet. 14: 429-435, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15601645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15601645</a>] [<a href="https://doi.org/10.1093/hmg/ddi039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15601645">Meikle et al. (2005)</a> proposed that these differences may be due to the timing of loss of Tsc1 in the ventricular myocytes and/or the truncated gestational period in the mouse compared with humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15601645" 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="#63" class="mim-tip-reference" title="Wilson, C., Idziaszczyk, S., Parry, L., Guy, C., Griffiths, D. F. R., Lazda, E., Bayne, R. A. L., Smith, A. J. H., Sampson, J. R., Cheadle, J. P. <strong>A mouse model of tuberous sclerosis 1 showing background specific early post-natal mortality and metastatic renal cell carcinoma.</strong> Hum. Molec. Genet. 14: 1839-1850, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15888477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15888477</a>] [<a href="https://doi.org/10.1093/hmg/ddi190" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15888477">Wilson et al. (2005)</a> showed that approximately 27% of Tsc1 +/- mice on a C57BL/6 background died at 1 to 2 days from unknown causes. Forty-four percent of Tsc1 +/- mice on a C3H background developed macroscopically visible renal lesions as early as 3 to 6 months, increasing to 95% by 15 to 18 months. Renal lesions progressed from cysts through cystadenomas to solid carcinomas. Eighty percent of Tsc1 +/- mice on a Balb/c background exhibited solid renal cell carcinomas by 15 to 18 months, and lesions showed loss of the wildtype Tsc1 allele and elevated protein levels of MTOR and RPS6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15888477" 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="#20" class="mim-tip-reference" title="Goorden, S. M. I., van Woerden, G. M., van der Weerd, L., Cheadle, J. P., Elgersma, Y. <strong>Cognitive deficits in Tsc1(+/-) mice in the absence of cerebral lesions and seizures.</strong> Ann. Neurol. 62: 648-655, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18067135/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18067135</a>] [<a href="https://doi.org/10.1002/ana.21317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18067135">Goorden et al. (2007)</a> found that Tsc1 +/- mice had no spontaneous seizures or cerebral lesions but showed impaired learning in hippocampus-sensitive versions of learning tasks and impaired social behavior. The findings indicated that haploinsufficiency for Tsc1 resulted in a functional neuronal deficit in the absence of overt cerebral pathology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18067135" 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="#66" class="mim-tip-reference" title="Zeng, L.-H., Xu, L., Gutmann, D. H., Wong, M. <strong>Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex.</strong> Ann. Neurol. 63: 444-453, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18389497/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18389497</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18389497[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/10.1002/ana.21331" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18389497">Zeng et al. (2008)</a> observed that mice with conditional Tsc1 inactivation primarily in glia developed glial proliferation, enlarged brain size, progressive epilepsy, and premature death. Treatment with rapamycin at postnatal day 14 before the onset of neurologic symptoms prevented the development of epilepsy and premature death. Treatment at 6 weeks, after the onset of symptoms, suppressed seizures and prolonged survival. Brain histology showed that treatment with rapamycin resulted in decreased abnormal astrocyte proliferation and increased neuronal organization compared to untreated mice, even at later treatment. Rapamycin caused a dose-dependent decrease in S6 phosphorylation, indicating inhibition of the MTOR pathway. Cessation of rapamycin treatment resulted in reappearance of seizures, progressive brain enlargement, and premature death, similar to untreated mice. <a href="#66" class="mim-tip-reference" title="Zeng, L.-H., Xu, L., Gutmann, D. H., Wong, M. <strong>Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex.</strong> Ann. Neurol. 63: 444-453, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18389497/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18389497</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18389497[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/10.1002/ana.21331" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18389497">Zeng et al. (2008)</a> concluded that rapamycin has strong efficacy for preventing seizures and prolonging survival in these transgenic mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18389497" 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>Independently, <a href="#1" class="mim-tip-reference" title="Abs, E., Goorden, S. M. I., Schreiber, J., Overwater, I. E., Hoogeveen-Westerveld, M., Bruinsma, C. F., Aganovic, E., Borgesius, N. Z., Nellist, M., Elgersma, Y. <strong>TORC1-dependent epilepsy caused by acute biallelic Tsc1 deletion in adult mice.</strong> Ann. Neurol. 74: 569-579, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23720219/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23720219</a>] [<a href="https://doi.org/10.1002/ana.23943" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23720219">Abs et al. (2013)</a> found that induced deletion of Tsc1 in adult mice resulted in activation of the MTOR complex-1 (TORC1) pathway and epilepsy. Prior to seizure onset, mutant mice showed enhanced neuronal excitability and decreased threshold for long-term potentiation. Rapamycin treatment reduced TORC1 activity and abolished seizures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23720219" 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>Patients with tuberous sclerosis often develop renal cysts and those with inherited codeletions of PKD1 gene (<a href="/entry/601313">601313</a>) develop severe, early-onset polycystic kidneys. Using mouse models, <a href="#10" class="mim-tip-reference" title="Bonnet, C. S., Aldred, M., von Ruhland, C., Harris, R., Sandford, R., Cheadle, J. P. <strong>Defects in cell polarity underlie TSC and ADPKD-associated cystogenesis.</strong> Hum. Molec. Genet. 18: 2166-2176, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19321600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19321600</a>] [<a href="https://doi.org/10.1093/hmg/ddp149" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19321600">Bonnet et al. (2009)</a> showed that many of the earliest lesions from Tsc1 +/-, Tsc2 +/-, and Pkd1 +/- mice did not exhibit activation of mTOR (<a href="/entry/601231">601231</a>), confirming an mTOR-independent pathway of renal cystogenesis. Using Tsc1/Pkd1 and Tsc2/Pkd1 heterozygous double-mutants, the authors showed functional cooperation and an effect on renal primary cilium length between hamartin and tuberin with polycystin-1. The Tsc1, Tsc2, and Pkd1 gene products helped regulate primary cilia length in renal tubules, renal epithelial cells, and precystic hepatic cholangiocytes. Consistent with the function of cilia in modulating cell polarity, <a href="#10" class="mim-tip-reference" title="Bonnet, C. S., Aldred, M., von Ruhland, C., Harris, R., Sandford, R., Cheadle, J. P. <strong>Defects in cell polarity underlie TSC and ADPKD-associated cystogenesis.</strong> Hum. Molec. Genet. 18: 2166-2176, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19321600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19321600</a>] [<a href="https://doi.org/10.1093/hmg/ddp149" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19321600">Bonnet et al. (2009)</a> found that many dividing precystic renal tubule and hepatic bile duct cells from Tsc1, Tsc2, and Pkd1 heterozygous mice were highly misoriented. <a href="#10" class="mim-tip-reference" title="Bonnet, C. S., Aldred, M., von Ruhland, C., Harris, R., Sandford, R., Cheadle, J. P. <strong>Defects in cell polarity underlie TSC and ADPKD-associated cystogenesis.</strong> Hum. Molec. Genet. 18: 2166-2176, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19321600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19321600</a>] [<a href="https://doi.org/10.1093/hmg/ddp149" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19321600">Bonnet et al. (2009)</a> proposed that defects in cell polarity may underlie cystic disease associated with TSC1, TSC2, and PKD1, and that targeting of this pathway may be of key therapeutic benefit. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19321600" 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="#68" class="mim-tip-reference" title="Zhou, J., Brugarolas, J., Parada, L. F. <strong>Loss of Tsc1, but not Pten, in renal tubular cells causes polycystic kidney disease by activating mTORC1.</strong> Hum. Molec. Genet. 18: 4428-4441, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19692352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19692352</a>] [<a href="https://doi.org/10.1093/hmg/ddp398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19692352">Zhou et al. (2009)</a> developed a polycystic kidney disease (PKD) mouse model by knocking out Tsc1 in a subset of renal tubular cells. Extensive renal cyst formation in these mice was accompanied by broadly elevated mammalian target of rapamycin complex-1 (mTORC1; <a href="/entry/607536">607536</a>) activity in both cell-autonomous and non-cell-autonomous compartments. Cyst development required mTORC1 activation, as low dosage of rapamycin administration effectively blocked cyst formation. Disruption of Pten (<a href="/entry/601728">601728</a>), an upstream regulator of Tsc1/Tsc2, in the same cells did not lead to PKD, seemingly due to limited activation of mTORC1, suggesting to the authors that PTEN may not be a major upstream regulator of TSC/mTORC1 during early postnatal kidney development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19692352" 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 mutant mice lacking the Tsc1 gene in oocytes, <a href="#2" class="mim-tip-reference" title="Adhikari, D., Zheng, W., Shen, Y., Gorre, N., Hamalainen, T., Cooney, A. J., Huhtaniemi, I., Lan, Z.-J., Liu, K. <strong>Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles.</strong> Hum. Molec. Genet. 19: 397-410, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19843540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19843540</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19843540[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/hmg/ddp483" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19843540">Adhikari et al. (2010)</a> showed that the entire pool of primordial follicles was activated prematurely due to elevated mTORC1 activity in the oocyte, resulting in follicular depletion in early adulthood and premature ovarian failure (POF). Maintenance of the quiescence of primordial follicles required synergistic, collaborative functioning of both Tsc1 and Pten, and these 2 molecules suppressed follicular activation through distinct ways. <a href="#2" class="mim-tip-reference" title="Adhikari, D., Zheng, W., Shen, Y., Gorre, N., Hamalainen, T., Cooney, A. J., Huhtaniemi, I., Lan, Z.-J., Liu, K. <strong>Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles.</strong> Hum. Molec. Genet. 19: 397-410, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19843540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19843540</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19843540[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/hmg/ddp483" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19843540">Adhikari et al. (2010)</a> concluded that Tsc/mTORC1 signaling and PTEN/PI3K (see <a href="/entry/171834">171834</a>) signaling synergistically regulate the dormancy and activation of primordial follicles, and together ensure the proper length of female reproductive life. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19843540" 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="#57" class="mim-tip-reference" title="Tsai, P. T., Hull, C., Chu, Y., Greene-Colozzi, E., Sadowski, A. R., Leech, J. M., Steinberg, J., Crawley, J. N., Regehr, W. G., Sahin, M. <strong>Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice.</strong> Nature 488: 647-651, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22763451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22763451</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22763451[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/nature11310" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22763451">Tsai et al. (2012)</a> showed that both heterozygous and homozygous loss of Tsc1 in mouse cerebellar Purkinje cells results in autistic-like behaviors, including abnormal social interaction, repetitive behavior, and vocalizations, in addition to decreased Purkinje cell excitability. Treatment of mutant mice with the mTOR inhibitor rapamycin prevented the pathologic and behavioral deficits. <a href="#57" class="mim-tip-reference" title="Tsai, P. T., Hull, C., Chu, Y., Greene-Colozzi, E., Sadowski, A. R., Leech, J. M., Steinberg, J., Crawley, J. N., Regehr, W. G., Sahin, M. <strong>Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice.</strong> Nature 488: 647-651, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22763451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22763451</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22763451[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/nature11310" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22763451">Tsai et al. (2012)</a> concluded that their findings demonstrated new roles for Tsc1 in Purkinje cell function and defined a molecular basis for a cerebellar contribution to cognitive disorders such as autism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22763451" 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="#39" class="mim-tip-reference" title="Lim, J. S., Gopalappa, R., Kim, S. H., Ramakrishna, S., Lee, M., Kim, W., Kim, J., Park, S. M., Lee, J., Oh, J.-H., Kim, H. D., Park, C.-H., Lee, J. S., Kim, S., Kim, D. S., Han, J. M., Kang, H.-C., Kim, H., Lee, J. H. <strong>Somatic mutations in TSC1 and TSC2 cause focal cortical dysplasia.</strong> Am. J. Hum. Genet. 100: 454-472, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28215400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28215400</a>] [<a href="https://doi.org/10.1016/j.ajhg.2017.01.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28215400">Lim et al. (2017)</a> demonstrated that knockdown of the Tsc1 gene in developing mouse neurons, using the CRISPR/CASP9 somatic genome editing method in utero, resulted in abnormal neuronal phenotypes resembling focal cortical dysplasia type II in humans, hyperactivation of the mTOR pathway, and epileptic seizures in mice. There was also evidence of abnormal radial migration of cortical neurons in CRISPR-treated neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28215400" 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="#18" class="mim-tip-reference" title="Ercan, E., Han, J. M., Di Nardo, A., Winden, K., Han, M.-J., Hoyo, L., Saffari, A., Leask, A., Geschwind, D. H., Sahin, M. <strong>Neuronal CTGF/CCN2 negatively regulates myelination in a mouse model of tuberous sclerosis complex.</strong> J. Exp. Med. 214: 681-697, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28183733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28183733</a>] [<a href="https://doi.org/10.1084/jem.20160446" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28183733">Ercan et al. (2017)</a> found that loss of Tsc1/Tsc2 in mouse neurons resulted in a block in oligodendrocyte development in vitro and in oligodendrocyte hypomyelination in vivo. These processes were mediated by neuronal Ctgf (<a href="/entry/121009">121009</a>), which was highly expressed and secreted from Tsc-deficient neurons and blocked development of oligodendrocytes. Expression of Srf (<a href="/entry/600589">600589</a>), the transcriptional regulator of Ctgf, was also decreased in Tsc-deficient neurons. Myelination could be improved by genetic ablation of Ctgf in neurons lacking Tsc1. Electron microscopy analysis suggested that this rescue of myelination was caused by the rescue of myelinated axon numbers, rather than changes in myelin thickness. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28183733" 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>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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</span>
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<strong>11 Selected Examples</a>):</strong>
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<div id="mimAllelicVariantsFold" class="collapse in mimTextToggleFold">
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<a href="/allelicVariants/605284" class="btn btn-default" role="button"> Table View </a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=605284[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<a id="0001" class="mim-anchor"></a>
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<strong>.0001 TUBEROUS SCLEROSIS 1</strong>
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</h4>
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TSC1, 4-BP DEL, 2105AAAG
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000005403 OR RCV000042099 OR RCV000189868" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005403, RCV000042099, RCV000189868" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005403...</a>
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<p><a href="#60" class="mim-tip-reference" title="van Slegtenhorst, M., de Hoogt, R., Hermans, C., Nellist, M., Janssen, B., Verhoef, S., Lindhout, D., van den Ouweland, A., Halley, D., Young, J., Burley, M., Jeremiah, S., and 29 others. <strong>Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34.</strong> Science 277: 805-808, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9242607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9242607</a>] [<a href="https://doi.org/10.1126/science.277.5327.805" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9242607">Van Slegtenhorst et al. (1997)</a> found a 4-bp deletion in exon 15 of the TSC1 gene (2105delAAAG) in 6 apparently unrelated individuals with tuberous sclerosis (<a href="/entry/191100">191100</a>). Four were familial and 2 were sporadic. In 2 familial cases with the deletion and a sporadic case, haplotype analysis using flanking markers confirmed an independent origin of the 3 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9242607" 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 id="0002" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0002 TUBEROUS SCLEROSIS 1</strong>
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</h4>
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TSC1, LEU250TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs118203447 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118203447;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=rs118203447" 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=rs118203447" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000005404 OR RCV000042356" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005404, RCV000042356" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005404...</a>
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<p>In a patient with tuberous sclerosis-1 (<a href="/entry/191100">191100</a>), <a href="#60" class="mim-tip-reference" title="van Slegtenhorst, M., de Hoogt, R., Hermans, C., Nellist, M., Janssen, B., Verhoef, S., Lindhout, D., van den Ouweland, A., Halley, D., Young, J., Burley, M., Jeremiah, S., and 29 others. <strong>Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34.</strong> Science 277: 805-808, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9242607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9242607</a>] [<a href="https://doi.org/10.1126/science.277.5327.805" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9242607">van Slegtenhorst et al. (1997)</a> identified a nonsense mutation in the TSC1 gene, a T-to-G transversion of nucleotide 970 leading to termination at amino acid 250. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9242607" 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 id="0003" class="mim-anchor"></a>
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<strong>.0003 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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</h4>
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TSC1, LYS587ARG
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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> rs118203576 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118203576;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/rs118203576?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=rs118203576" 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=rs118203576" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000005405 OR RCV000042078 OR RCV000118691 OR RCV000163265 OR RCV000224245 OR RCV000303027" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005405, RCV000042078, RCV000118691, RCV000163265, RCV000224245, RCV000303027" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005405...</a>
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<span class="mim-text-font">
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<p>This variant, formerly titled TUBEROUS SCLEROSIS 1, has been reclassified based on the findings of <a href="#34" class="mim-tip-reference" title="Kwiatkowska, J., Jozwiak, S., Hall, F., Henske, E. P., Haines, J. L., McNamara, P., Braiser, J., Wigowska-Sowinska, J., Kasprzyk-Obara, J., Short, M. P., Kwiatkowski, D. J. <strong>Comprehensive mutational analysis of the TSC1 gene: observations on frequency of mutation, associated features, and nonpenetrance.</strong> Ann. Hum. Genet. 62: 277-285, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9924605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9924605</a>] [<a href="https://doi.org/10.1046/j.1469-1809.1998.6240277.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9924605">Kwiatkowska et al. (1998)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9924605" 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 patients with tuberous sclerosis-1 (<a href="/entry/191100">191100</a>), the only missense mutation among the 32 mutations found by <a href="#60" class="mim-tip-reference" title="van Slegtenhorst, M., de Hoogt, R., Hermans, C., Nellist, M., Janssen, B., Verhoef, S., Lindhout, D., van den Ouweland, A., Halley, D., Young, J., Burley, M., Jeremiah, S., and 29 others. <strong>Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34.</strong> Science 277: 805-808, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9242607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9242607</a>] [<a href="https://doi.org/10.1126/science.277.5327.805" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9242607">van Slegtenhorst et al. (1997)</a> in the TSC1 gene was an A-to-G transition at nucleotide 1981, leading to a lys585-to-arg (K585R) amino acid change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9242607" 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="#34" class="mim-tip-reference" title="Kwiatkowska, J., Jozwiak, S., Hall, F., Henske, E. P., Haines, J. L., McNamara, P., Braiser, J., Wigowska-Sowinska, J., Kasprzyk-Obara, J., Short, M. P., Kwiatkowski, D. J. <strong>Comprehensive mutational analysis of the TSC1 gene: observations on frequency of mutation, associated features, and nonpenetrance.</strong> Ann. Hum. Genet. 62: 277-285, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9924605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9924605</a>] [<a href="https://doi.org/10.1046/j.1469-1809.1998.6240277.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9924605">Kwiatkowska et al. (1998)</a> identified the c.1981A-G mutation in the TSC1 gene, which they stated resulted in a K587R substitution, in a patient with sporadic TSC and his unaffected parent, suggesting that the variant is nonpathogenic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9924605" 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 id="0004" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0004 TUBEROUS SCLEROSIS 1</strong>
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TSC1, 2-BP DEL, 2122AC
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs118203597 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118203597;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=rs118203597" 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=rs118203597" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000005406 OR RCV000042102 OR RCV000713907 OR RCV003162210 OR RCV004797756" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005406, RCV000042102, RCV000713907, RCV003162210, RCV004797756" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005406...</a>
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<p><a href="#35" class="mim-tip-reference" title="Kwiatkowska, J., Wigowska-Sowinska, J., Napierala, D., Slomski, R., Kwiatkowski, D. J. <strong>Mosaicism in tuberous sclerosis as a potential cause of the failure of molecular diagnosis.</strong> New Eng. J. Med. 340: 703-707, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10053179/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10053179</a>] [<a href="https://doi.org/10.1056/NEJM199903043400905" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10053179">Kwiatkowska et al. (1999)</a> described a patient with severe tuberous sclerosis (<a href="/entry/191100">191100</a>) in whom a mutated TSC1 allele was present in only one-third of leukocytes and in different proportions in other tissues. The case illustrated the importance of considering mosaicism and the limitation of molecular diagnostic methods. The infant girl was born to young healthy parents. Her development was normal until the age of 18 months, when myoclonic seizures occurred. Although the seizures stopped with corticotropin therapy, the child subsequently learned few additional words and withdrew from interaction with her parents and others. At the age of 12 years, she began to have absence seizures. Evaluation revealed a normal body habitus but limited activity and diminished social interaction. Formal testing showed an IQ score of less than 40. Several angiofibromas were present in the malar regions of the face. MRI and CT of the brain showed several calcified subependymal nodules, 2 large cortical tubers (one of which was calcified), and many smaller cortical tubers. Results of renal ultrasonography, echocardiography, and retinal examination were all normal. In exon 15 of the TSC1 gene, a 2-bp deletion, 2122delAC, was found. This deletion changed the TSC1 protein sequence after amino acid residue 634 and truncated it at residue 685; in contrast, the normal TSC1 protein has 1164 residues. DNA from urine and hair roots formed heteroduplexes, indicating that they contained the mutant allele. However, a sample of buccal-mucosa DNA had no heteroduplex product, suggesting that the mutant allele was absent in that sample. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10053179" 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 TUBEROUS SCLEROSIS 1</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">rs118203557 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118203557;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=rs118203557" 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=rs118203557" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000005407 OR RCV000054946 OR RCV000713905" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005407, RCV000054946, RCV000713905" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005407...</a>
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<p><a href="#55" class="mim-tip-reference" title="Smith, M., Sperling, D. <strong>Novel 23-base-pair duplication mutation in TSC1 exon 15 in an infant presenting with cardiac rhabdomyomas.</strong> Am. J. Med. Genet. 84: 346-349, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10340649/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10340649</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19990604)84:4<346::aid-ajmg7>3.0.co;2-e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10340649">Smith and Sperling (1999)</a> reported the results of mutation analysis in a sporadic case of tuberous sclerosis (<a href="/entry/191100">191100</a>) first identified in intrauterine life on the basis of the presence of cardiac rhabdomyomas. Postnatally, this infant was also found to have subependymal nodules on brain computed tomographic scan. Hypomelanotic macules were not detected neonatally or at 12 months of age. The specific mutation identified in this patient was duplication of a 23-bp segment of DNA between two 9-bp repeated sequence elements within exon 15 of the TSC1 gene. These repeat elements were located between nucleotides 1892 and 1900 and between nucleotides 1915 and 1923. <a href="#55" class="mim-tip-reference" title="Smith, M., Sperling, D. <strong>Novel 23-base-pair duplication mutation in TSC1 exon 15 in an infant presenting with cardiac rhabdomyomas.</strong> Am. J. Med. Genet. 84: 346-349, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10340649/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10340649</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19990604)84:4<346::aid-ajmg7>3.0.co;2-e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10340649">Smith and Sperling (1999)</a> considered it likely that the presence of these 2 repeated elements predisposed to misalignment of DNA strands and unequal crossing-over. The mechanism of origin of rhabdomyomas in tuberous sclerosis was reviewed. Loss of heterozygosity in the tuberous sclerosis gene regions had been reported in cardiac rhabdomyomas; however, these lesions are self limiting in their growth. The basis for this self-limiting proliferation was not clear. One interesting postulation was that cardiac rhabdomyomas may be due to delay or failure of apoptosis which occurs as part of the normal remodeling process in the heart. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10340649" 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">rs118203388 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118203388;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=rs118203388" 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=rs118203388" 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 Japanese patient with isolated pulmonary lymphangioleiomyomatosis (LAM; <a href="/entry/606690">606690</a>), <a href="#53" class="mim-tip-reference" title="Sato, T., Seyama, K., Fujii, H., Maruyama, H., Setoguchi, Y., Iwakami, S., Fukuchi, Y., Hino, O. <strong>Mutation analysis of the TSC1 and TSC2 genes in Japanese patients with pulmonary lymphangioleiomyomatosis.</strong> J. Hum. Genet. 47: 20-28, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11829138/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11829138</a>] [<a href="https://doi.org/10.1007/s10038-002-8651-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11829138">Sato et al. (2002)</a> identified a C-to-A transversion at nucleotide 716 in exon 6 of the TSC1 gene, resulting in a cys165-to-ter mutation. Complete inactivation of the TSC1 gene concordant with the Knudson tumor suppressor model (<a href="#32" class="mim-tip-reference" title="Knudson, A. G., Jr. <strong>Mutation and cancer: statistical study of retinoblastoma.</strong> Proc. Nat. Acad. Sci. 68: 820-823, 1971.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5279523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5279523</a>] [<a href="https://doi.org/10.1073/pnas.68.4.820" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5279523">Knudson, 1971</a>) was observed in this patient, who had a TSC1 germline mutation and TSC1 LOH for 2 chromosome 9 markers, D9S149 and D9S1198. Since there was a germline mutation in this case, the isolated pulmonary LAM could be considered monosymptomatic TSC; however, the patient had no clinical features characteristic of TSC. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5279523+11829138" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs118203657 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118203657;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/rs118203657?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=rs118203657" 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=rs118203657" 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=RCV000005409 OR RCV000005410 OR RCV000034607 OR RCV000054851 OR RCV000118692 OR RCV000129684 OR RCV000278906" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005409, RCV000005410, RCV000034607, RCV000054851, RCV000118692, RCV000129684, RCV000278906" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005409...</a>
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<p>This variant, formerly titled FOCAL CORTICAL DYSPLASIA OF TAYLOR, TYPE IIB and TUBEROUS SCLEROSIS 1, has been reclassified based on the findings of <a href="#23" class="mim-tip-reference" title="Gumbinger, C., Rohsbach, C. B., Schulze-Bonhage, A., Korinthenberg, R., Zentner, J., Haffner, M., Fauser, S. <strong>Focal cortical dysplasia: a genotype-phenotype analysis of polymorphisms and mutations in the TSC genes.</strong> Epilepsia 50: 1396-1408, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19175396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19175396</a>] [<a href="https://doi.org/10.1111/j.1528-1167.2008.01979.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19175396">Gumbinger et al. (2009)</a> and <a href="#51" class="mim-tip-reference" title="Rendtorff, N. D., Bjerregaard, B., Frodin, M., Kjaergaard, S., Hove, H., Skovby, F., the Danish Tuberous Sclerosis Group, Brondum-Nielsen, K., Schwartz, M. <strong>Analysis of 65 tuberous sclerosis complex (TSC) patients by TSC2 DGGE, TSC1/TSC2 MLPA, and TSC1 long-range PCR sequencing, and report of 28 novel mutations.</strong> Hum. Mutat. 26: 374-383, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16114042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16114042</a>] [<a href="https://doi.org/10.1002/humu.20227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16114042">Rendtorff et al. (2005)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16114042+19175396" 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="Becker, A. J., Urbach, H., Scheffler, B., Baden, T., Normann, S., Lahl, R., Pannek, H. W., Tuxhorn, I., Elger, C. E., Schramm, J., Wiestler, O. D., Blumcke, I. <strong>Focal cortical dysplasia of Taylor's balloon cell type: mutational analysis of the TSC1 gene indicates a pathogenic relationship to tuberous sclerosis.</strong> Ann. Neurol. 52: 29-37, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12112044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12112044</a>] [<a href="https://doi.org/10.1002/ana.10251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12112044">Becker et al. (2002)</a> showed that an amino acid change in residue 732 of hamartin from histidine to tyrosine (H732Y) was present in 14 of 40 (35%) cases of focal cortical dysplasia of the Taylor balloon cell type (see <a href="/entry/607341">607341</a>) as compared with 2 of 200 (1%) controls. The change was produced by a C-to-T transition at nucleotide 2415 in exon 17 of the TSC1 gene. Exon 17 was the site of a number of other polymorphisms associated with focal cortical dysplasia, as were exons 14 and 22. The H732Y mutation had previously been observed at low frequencies in tuberous sclerosis (<a href="/entry/191100">191100</a>) and in unaffected individuals (<a href="#30" class="mim-tip-reference" title="Jones, A. C., Daniells, C. E., Snell, R. G., Tachataki, M., Idziaszczyk, S. A., Krawczak, M., Sampson, J. R., Cheadle, J. P. <strong>Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis.</strong> Hum. Molec. Genet. 6: 2155-2161, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9328481/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9328481</a>] [<a href="https://doi.org/10.1093/hmg/6.12.2155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9328481">Jones et al., 1997</a>; <a href="#62" class="mim-tip-reference" title="van Slegtenhorst, M., Verhoef, S., Tempelaars, A., Bakker, L., Wang, Q., Wessels, M., Bakker, R., Nellist, M., Lindhout, D., Halley, D., van den Ouweland, A. <strong>Mutational spectrum of the TSC1 gene in a cohort of 225 tuberous sclerosis complex patients: no evidence for genotype-phenotype correlation.</strong> J. Med. Genet. 36: 285-289, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10227394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10227394</a>]" pmid="10227394">van Slegtenhorst et al., 1999</a>). <a href="#6" class="mim-tip-reference" title="Becker, A. J., Urbach, H., Scheffler, B., Baden, T., Normann, S., Lahl, R., Pannek, H. W., Tuxhorn, I., Elger, C. E., Schramm, J., Wiestler, O. D., Blumcke, I. <strong>Focal cortical dysplasia of Taylor's balloon cell type: mutational analysis of the TSC1 gene indicates a pathogenic relationship to tuberous sclerosis.</strong> Ann. Neurol. 52: 29-37, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12112044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12112044</a>] [<a href="https://doi.org/10.1002/ana.10251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12112044">Becker et al. (2002)</a> interpreted the change and others as germline polymorphisms that predispose toward the cerebral lesion when combined with LOH in the other allele. The H732T substitution is located in a region of the hamartin protein involved in the interaction domain with tuberin, the product of the TSC2 gene (<a href="/entry/191092">191092</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9328481+12112044+10227394" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a detailed genotype-phenotype analysis of 33 patients with focal cortical dysplasia, including 23 with FCD type II, <a href="#23" class="mim-tip-reference" title="Gumbinger, C., Rohsbach, C. B., Schulze-Bonhage, A., Korinthenberg, R., Zentner, J., Haffner, M., Fauser, S. <strong>Focal cortical dysplasia: a genotype-phenotype analysis of polymorphisms and mutations in the TSC genes.</strong> Epilepsia 50: 1396-1408, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19175396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19175396</a>] [<a href="https://doi.org/10.1111/j.1528-1167.2008.01979.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19175396">Gumbinger et al. (2009)</a> identified several sequence variations in the TSC1 and TSC2 genes in both lesional brain tissue and blood of the patients, but in similar frequencies to that of the normal population. Most of the sequence alterations were silent. <a href="#23" class="mim-tip-reference" title="Gumbinger, C., Rohsbach, C. B., Schulze-Bonhage, A., Korinthenberg, R., Zentner, J., Haffner, M., Fauser, S. <strong>Focal cortical dysplasia: a genotype-phenotype analysis of polymorphisms and mutations in the TSC genes.</strong> Epilepsia 50: 1396-1408, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19175396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19175396</a>] [<a href="https://doi.org/10.1111/j.1528-1167.2008.01979.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19175396">Gumbinger et al. (2009)</a> concluded that focal cortical dysplasia is not caused by mutation in the TSC genes and does not appear to be promoted by TSC polymorphisms. <a href="#51" class="mim-tip-reference" title="Rendtorff, N. D., Bjerregaard, B., Frodin, M., Kjaergaard, S., Hove, H., Skovby, F., the Danish Tuberous Sclerosis Group, Brondum-Nielsen, K., Schwartz, M. <strong>Analysis of 65 tuberous sclerosis complex (TSC) patients by TSC2 DGGE, TSC1/TSC2 MLPA, and TSC1 long-range PCR sequencing, and report of 28 novel mutations.</strong> Hum. Mutat. 26: 374-383, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16114042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16114042</a>] [<a href="https://doi.org/10.1002/humu.20227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16114042">Rendtorff et al. (2005)</a> considered the H732Y mutation, which had been identified by <a href="#30" class="mim-tip-reference" title="Jones, A. C., Daniells, C. E., Snell, R. G., Tachataki, M., Idziaszczyk, S. A., Krawczak, M., Sampson, J. R., Cheadle, J. P. <strong>Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis.</strong> Hum. Molec. Genet. 6: 2155-2161, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9328481/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9328481</a>] [<a href="https://doi.org/10.1093/hmg/6.12.2155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9328481">Jones et al. (1997)</a> in individuals without tuberous sclerosis, to be a polymorphism. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9328481+16114042+19175396" 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">rs118203426 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118203426;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=rs118203426" 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=rs118203426" 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=RCV000005411 OR RCV000042336" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005411, RCV000042336" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005411...</a>
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<p>In 4 affected individuals from a family with tuberous sclerosis (<a href="/entry/191100">191100</a>), <a href="#44" class="mim-tip-reference" title="Nellist, M., van den Heuvel, D., Schluep, D., Exalto, C., Goedbloed, M., Maat-Kievit, A., van Essen, T., van Spaendonck-Zwarts, K., Jansen, F., Helderman, P., Bartalini, G., Vierimaa, O., Penttinen, M., van den Ende, J., van den Ouweland, A., Halley, D. <strong>Missense mutations to the TSC1 gene cause tuberous sclerosis complex.</strong> Europ. J. Hum. Genet. 17: 319-328, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18830229/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18830229</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18830229[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/ejhg.2008.170" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18830229">Nellist et al. (2009)</a> identified a heterozygous 671T-G transversion in the TSC1 gene, resulting in a met224-to-arg (M224R) substitution. The proband had definite TSC with multiple shagreen patches, hypomelanotic macules, ungual fibromas, dental pits, epilepsy and severe mental disability. One parent and both siblings also fulfilled the diagnostic criteria for definite TSC, including seizures, cortical tubers, and below-average intelligence. All affected individuals also carried a neutral 3103G-A polymorphism (gly1035 to ser; G1035S) in cis with the M224R mutation. In vitro functional expression studies showed that M224R-mutant protein did not decrease phosphorylation of p70-S6K (<a href="/entry/608938">608938</a>), indicating constitutive activation of the MTOR (FRAP1; <a href="/entry/601231">601231</a>)-S6K pathway, whereas the G1035S variant and wildtype protein reduced S6K phosphorylation. These findings indicated that M224R mutation was responsible for the phenotype in this family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18830229" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 TUBEROUS SCLEROSIS 1</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">rs118203396 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs118203396;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=rs118203396" 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=rs118203396" 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=RCV000005412 OR RCV000042306" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005412, RCV000042306" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005412...</a>
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<p>In 5 affected individuals from a 3-generation family with tuberous sclerosis (<a href="/entry/191100">191100</a>), <a href="#44" class="mim-tip-reference" title="Nellist, M., van den Heuvel, D., Schluep, D., Exalto, C., Goedbloed, M., Maat-Kievit, A., van Essen, T., van Spaendonck-Zwarts, K., Jansen, F., Helderman, P., Bartalini, G., Vierimaa, O., Penttinen, M., van den Ende, J., van den Ouweland, A., Halley, D. <strong>Missense mutations to the TSC1 gene cause tuberous sclerosis complex.</strong> Europ. J. Hum. Genet. 17: 319-328, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18830229/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18830229</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18830229[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/ejhg.2008.170" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18830229">Nellist et al. (2009)</a> identified a heterozygous 539T-C transition in the TSC1 gene, resulting in a leu180-to-pro (L180P) substitution. In vitro functional expression studies detected the mutant protein at low levels and showed that the mutant protein did not inhibit S6K (<a href="/entry/608938">608938</a>) phosphorylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18830229" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 FOCAL CORTICAL DYSPLASIA, TYPE II, SOMATIC</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> rs749030456 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs749030456;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/rs749030456?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=rs749030456" 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=rs749030456" 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=RCV000477710 OR RCV000573120 OR RCV000695216 OR RCV001526808 OR RCV001721544" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000477710, RCV000573120, RCV000695216, RCV001526808, RCV001721544" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000477710...</a>
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<p>In brain tissue resected from 3 unrelated children (FCD81, FCD98, FCD123) with seizures due to focal cortical dysplasia type II (FCORD2; <a href="/entry/607341">607341</a>), <a href="#39" class="mim-tip-reference" title="Lim, J. S., Gopalappa, R., Kim, S. H., Ramakrishna, S., Lee, M., Kim, W., Kim, J., Park, S. M., Lee, J., Oh, J.-H., Kim, H. D., Park, C.-H., Lee, J. S., Kim, S., Kim, D. S., Han, J. M., Kang, H.-C., Kim, H., Lee, J. H. <strong>Somatic mutations in TSC1 and TSC2 cause focal cortical dysplasia.</strong> Am. J. Hum. Genet. 100: 454-472, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28215400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28215400</a>] [<a href="https://doi.org/10.1016/j.ajhg.2017.01.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28215400">Lim et al. (2017)</a> identified a de novo somatic c.64C-T transition (c.64C-T, NM_000368.4) in the TSC1 gene, resulting in an arg22-to-trp (R22W) substitution at a highly conserved residue. The mutation, which was found by targeted sequencing of genes in the MTOR pathway, was not found in the 1000 Genomes Project database, but was present at a very low frequency (1.65 x 10(-5)) in the ExAC database. The mutant allele frequency in brain tissue was very low, about 1 to 2.8%. Patient dystrophic brain cells and R22W-transfected cells showed increased S6K phosphorylation (RPS6KB1; <a href="/entry/608938">608938</a>) compared to wildtype, consistent with hyperactivation of the mTOR pathway. Mutant TSC1 also showed impaired binding to TSC2, indicating disruption of the TSC1-TSC2 complex. Abnormal S6K phosphorylation in transfected cells was inhibited by treatment with rapamycin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28215400" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 FOCAL CORTICAL DYSPLASIA, TYPE II, SOMATIC</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">rs1060505021 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1060505021;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=rs1060505021" 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=rs1060505021" 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=RCV000477742 OR RCV000694777" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000477742, RCV000694777" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000477742...</a>
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<p>In brain tissue resected from a 6-year-old girl (FCD64) with seizures due to focal cortical dysplasia type II (FCORD2; <a href="/entry/607341">607341</a>), <a href="#39" class="mim-tip-reference" title="Lim, J. S., Gopalappa, R., Kim, S. H., Ramakrishna, S., Lee, M., Kim, W., Kim, J., Park, S. M., Lee, J., Oh, J.-H., Kim, H. D., Park, C.-H., Lee, J. S., Kim, S., Kim, D. S., Han, J. M., Kang, H.-C., Kim, H., Lee, J. H. <strong>Somatic mutations in TSC1 and TSC2 cause focal cortical dysplasia.</strong> Am. J. Hum. Genet. 100: 454-472, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28215400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28215400</a>] [<a href="https://doi.org/10.1016/j.ajhg.2017.01.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28215400">Lim et al. (2017)</a> identified a de novo somatic c.610C-T transition (c.610C-T, NM_000368.4) in the TSC1 gene, resulting in an arg204-to-cys (R204C) substitution at a highly conserved residue. The mutation, which was found by targeted sequencing of genes in the MTOR pathway, was not found in the 1000 Genomes Project or ExAC databases. The mutant allele frequency in brain tissue was very low, less than 2%. Patient dystrophic brain cells and R204C-transfected cells showed increased S6K phosphorylation (RPS6KB1; <a href="/entry/608938">608938</a>) compared to wildtype, consistent with hyperactivation of the mTOR pathway. Mutant TSC1 also showed impaired binding to TSC2, indicating disruption of the TSC1-TSC2 complex. Abnormal S6K phosphorylation in transfected cells was inhibited by treatment with rapamycin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28215400" 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>REFERENCES</strong>
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Abs, E., Goorden, S. M. I., Schreiber, J., Overwater, I. E., Hoogeveen-Westerveld, M., Bruinsma, C. F., Aganovic, E., Borgesius, N. Z., Nellist, M., Elgersma, Y.
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<strong>TORC1-dependent epilepsy caused by acute biallelic Tsc1 deletion in adult mice.</strong>
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Ann. Neurol. 74: 569-579, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23720219/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23720219</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23720219" 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.23943" target="_blank">Full Text</a>]
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Adhikari, D., Zheng, W., Shen, Y., Gorre, N., Hamalainen, T., Cooney, A. J., Huhtaniemi, I., Lan, Z.-J., Liu, K.
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<strong>Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles.</strong>
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Hum. Molec. Genet. 19: 397-410, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19843540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19843540</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19843540[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=19843540" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddp483" target="_blank">Full Text</a>]
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Ali, J. B. M., Sepp, T., Ward, S., Green, A. J., Yates, J. R. W.
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<strong>Mutations in the TSC1 gene account for a minority of patients with tuberous sclerosis.</strong>
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J. Med. Genet. 35: 969-972, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9863590/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9863590</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9863590" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.35.12.969" target="_blank">Full Text</a>]
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Astrinidis, A., Senapedis, W., Henske, E. P.
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<strong>Hamartin, the tuberous sclerosis complex 1 gene product, interacts with polo-like kinase 1 in a phosphorylation-dependent manner.</strong>
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Hum. Molec. Genet. 15: 287-297, 2006.
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[<a href="https://doi.org/10.1093/hmg/ddi444" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1097/gim.0b013e31803068c7" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.10251" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(199911)14:5<428::AID-HUMU9>3.0.CO;2-5" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.onc.1204009" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddp149" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/3.10.1829" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-2264(199601)15:1<18::AID-GCC3>3.0.CO;2-7" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s003350010203" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/3.10.1833" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddp398" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Paul J. Converse - updated : 01/02/2018
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 04/06/2017<br>Patricia A. Hartz - updated : 02/17/2017<br>Carol A. Bocchini - updated : 1/7/2016<br>Ada Hamosh - updated : 10/1/2014<br>Ada Hamosh - updated : 11/2/2012<br>Ada Hamosh - updated : 9/18/2012<br>George E. Tiller - updated : 1/14/2011<br>George E. Tiller - updated : 10/4/2010<br>George E. Tiller - updated : 3/3/2010<br>Patricia A. Hartz - updated : 11/11/2009<br>George E. Tiller - updated : 10/23/2009<br>Cassandra L. Kniffin - updated : 9/24/2009<br>George E. Tiller - updated : 8/10/2009<br>Cassandra L. Kniffin - updated : 4/6/2009<br>Ada Hamosh - updated : 12/30/2008<br>Patricia A. Hartz - updated : 11/7/2008<br>George E. Tiller - updated : 10/28/2008<br>Patricia A. Hartz - updated : 4/28/2008<br>Cassandra L. Kniffin - updated : 4/4/2008<br>George E. Tiller - updated : 12/11/2007<br>Ada Hamosh - updated : 7/25/2007<br>Natalie E. Krasikov - updated : 7/29/2004<br>Cassandra L. Kniffin - updated : 11/6/2002<br>George E. Tiller - updated : 10/3/2002<br>Victor A. McKusick - updated : 9/18/2002<br>George E. Tiller - updated : 8/14/2002<br>Victor A. McKusick - updated : 2/11/2002<br>Victor A. McKusick - updated : 9/14/2001<br>Deborah L. Stone - updated : 9/12/2001<br>Paul J. Converse - updated : 8/13/2001<br>Stylianos E. Antonarakis - updated : 5/7/2001<br>Victor A. McKusick - updated : 1/23/2001<br>Victor A. McKusick - updated : 12/15/2000
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 9/25/2000
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 12/16/2020
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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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carol : 07/09/2019<br>mgross : 01/02/2018<br>carol : 04/11/2017<br>ckniffin : 04/06/2017<br>mgross : 02/17/2017<br>carol : 01/08/2016<br>carol : 1/7/2016<br>carol : 1/7/2016<br>alopez : 10/1/2014<br>carol : 9/16/2013<br>alopez : 11/5/2012<br>terry : 11/2/2012<br>alopez : 9/19/2012<br>terry : 9/18/2012<br>wwang : 1/14/2011<br>alopez : 10/22/2010<br>terry : 10/4/2010<br>wwang : 3/12/2010<br>terry : 3/3/2010<br>joanna : 11/23/2009<br>mgross : 11/13/2009<br>terry : 11/11/2009<br>wwang : 11/3/2009<br>terry : 10/23/2009<br>wwang : 10/21/2009<br>ckniffin : 9/24/2009<br>wwang : 8/13/2009<br>terry : 8/10/2009<br>carol : 6/19/2009<br>wwang : 4/15/2009<br>ckniffin : 4/6/2009<br>alopez : 1/5/2009<br>terry : 12/30/2008<br>mgross : 11/10/2008<br>terry : 11/7/2008<br>wwang : 10/28/2008<br>mgross : 4/28/2008<br>wwang : 4/14/2008<br>ckniffin : 4/4/2008<br>ckniffin : 2/5/2008<br>wwang : 12/28/2007<br>terry : 12/11/2007<br>terry : 8/9/2007<br>alopez : 8/2/2007<br>alopez : 8/1/2007<br>terry : 7/25/2007<br>carol : 8/29/2005<br>mgross : 9/23/2004<br>tkritzer : 8/27/2004<br>carol : 7/29/2004<br>carol : 7/29/2004<br>carol : 7/29/2004<br>ckniffin : 3/23/2004<br>joanna : 3/19/2004<br>carol : 1/28/2003<br>tkritzer : 12/10/2002<br>tkritzer : 12/6/2002<br>tkritzer : 12/4/2002<br>terry : 11/27/2002<br>tkritzer : 11/14/2002<br>alopez : 11/12/2002<br>carol : 11/12/2002<br>ckniffin : 11/6/2002<br>cwells : 10/3/2002<br>tkritzer : 9/23/2002<br>tkritzer : 9/19/2002<br>tkritzer : 9/18/2002<br>tkritzer : 9/18/2002<br>cwells : 8/14/2002<br>mgross : 2/14/2002<br>mgross : 2/14/2002<br>terry : 2/11/2002<br>mcapotos : 9/18/2001<br>mcapotos : 9/14/2001<br>carol : 9/12/2001<br>mgross : 8/13/2001<br>mgross : 5/7/2001<br>carol : 1/23/2001<br>terry : 1/23/2001<br>carol : 12/19/2000<br>terry : 12/15/2000<br>alopez : 10/19/2000<br>alopez : 10/9/2000<br>alopez : 9/25/2000
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<h3>
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<span class="mim-font">
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<strong>*</strong> 605284
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<div>
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<h3>
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<span class="mim-font">
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TSC COMPLEX SUBUNIT 1; TSC1
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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TSC1 GENE<br />
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HAMARTIN
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</span>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: TSC1</em></strong>
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</span>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 73017001;
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<strong>ICD10CM:</strong> J84.81;
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<strong>ICD9CM:</strong> 516.4;
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<strong>
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<em>
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Cytogenetic location: 9q34.13
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Genomic coordinates <span class="small">(GRCh38)</span> : 9:132,891,349-132,945,378 </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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<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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Location
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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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Inheritance
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<th>
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Phenotype <br /> mapping key
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<span class="mim-font">
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9q34.13
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<td>
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<span class="mim-font">
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Focal cortical dysplasia, type II, somatic
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</td>
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<span class="mim-font">
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607341
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</td>
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<td>
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<span class="mim-font">
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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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</td>
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<span class="mim-font">
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Lymphangioleiomyomatosis
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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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606690
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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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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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<tr>
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<td>
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<span class="mim-font">
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Tuberous sclerosis-1
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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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191100
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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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</td>
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<td>
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<span class="mim-font">
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3
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</td>
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</tr>
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</table>
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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 TSC1 gene encodes hamartin, a protein that interacts with tuberin (TSC2; 191092) to form a protein complex that inhibits signal transduction to the downstream effectors of the mammalian target of rapamycin (MTOR; 601231) (Inoki et al., 2002). </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>As part of a comprehensive strategy to identify the gene mutant in tuberous sclerosis-1 (191100), van Slegtenhorst et al. (1997) developed an overlapping contig of clones from the 1.4-Mb TSC1 region on chromosome 9. Several techniques showed the region to be gene-rich, with at least 30 genes in a 900-kb segment. They identified 142 exons and 13 genes between D9S1199 and D9S114. The authors PCR-amplified putative and confirmed exons in a set of 60 DNA samples from 40 sporadic tuberous sclerosis cases and 20 unrelated familial tuberous sclerosis patients showing linkage to 9q34. Van Slegtenhorst et al. (1997) identified mutations in an exon that was part of a transcriptional unit identified by earlier gene discovery efforts (Nagase et al., 1996). The predicted TSC1 protein, which was called 'hamartin' by van Slegtenhorst et al. (1997), consists of 1,164 amino acids and has a calculated mass of 130 kD. </p>
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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>The TSC1 gene consists of 23 exons, of which the last 21 contain coding sequence and the second is alternatively spliced (van Slegtenhorst et al., 1997). </p><p>Cheadle et al. (2000) described the genomic organization of the mouse Tsc1 locus. </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>Hamartin (TSC1), the protein that is defective in tuberous sclerosis-1, has no significant homology to tuberin (TSC2; 191092), the protein defective in tuberous sclerosis-2, which is a putative GTPase-activating protein for RAP1 (see 600278) and RAB5 (179512). Van Slegtenhorst et al. (1998) showed that hamartin and tuberin associate physically in vivo, however, and that the interaction is mediated by predicted coiled-coil domains. The data suggested to the authors that hamartin and tuberin function in the same complex rather than in separate pathways. </p><p>Benvenuto et al. (2000) showed that overexpression of the TSC1 gene in rat fibroblasts inhibits growth and causes changes in cell morphology. Growth inhibition was associated with an increase in the endogenous level of tuberin. As overexpression of tuberin inhibits cell growth, and hamartin is known to bind tuberin, these results suggested that hamartin stabilizes tuberin and that this contributes to the inhibition of cell growth. The stabilization was explained by the finding that tuberin is highly ubiquitinated in cells, while the fraction of tuberin that is bound to hamartin is not ubiquitinated. Coexpression of tuberin stabilized hamartin, which is weakly ubiquitinated, in transiently transfected cells. The amino-terminal two-thirds of tuberin was responsible for its ubiquitination and for stabilization of hamartin. A mutant of tuberin from a patient with a missense mutation of the TSC2 gene, N1658K, was also highly ubiquitinated, and was unable to stabilize hamartin. Benvenuto et al. (2000) concluded that hamartin is a growth inhibitory protein whose biologic effect is probably dependent on its interaction with tuberin. </p><p>Hodges et al. (2001) used a series of hamartin and tuberin constructs to assay for interaction in the yeast 2-hybrid system. Hamartin (amino acids 302-430) and tuberin (amino acids 1-418) interacted strongly with one another. A region of tuberin encoding a putative coiled-coil (amino acids 346-371) was necessary but not sufficient to mediate the interaction with hamartin, as more N-terminal residues were also required. A region of hamartin (amino acids 719-998) predicted to encode coiled-coils was capable of oligomerization but was not important for the interaction with tuberin. Subtle, non-truncating mutations identified in patients with tuberous sclerosis and located within the putative binding regions of hamartin or tuberin abolished or dramatically reduced interaction of the proteins. </p><p>Miloloza et al. (2000) showed that expression of hamartin, assayed by immunoblot analyses, is high in G0-arrested cells, although it is expressed throughout the entire ongoing cell cycle. In addition, ectopic expression of high levels of hamartin attenuated cellular proliferation. The authors proposed that hamartin affects cell proliferation via deregulation of G1 phase. </p><p>Activated ezrin (123900), radixin (179410), and moesin (309845) (ERM) family proteins promote linkages between integral membrane proteins and cytoskeleton proteins, such as F-actin (see ACTA1; 102610). In the inactive form, the N and C termini of the ERM protein interact, masking their membrane- and actin-interacting activities, respectively. Activation of ERM proteins requires RHO (see ARHA; 165390), which induces a cascade that results in the phosphorylation of threonine in the C terminus of the ERM protein and causes the intramolecular bond between the N and C termini to dissociate (Fukuhara and Gutkind, 2000). Lamb et al. (2000) used yeast 2-hybrid analysis to screen a mouse fibroblast cDNA library with ezrin as bait. Slot blot analysis, immunoprecipitation, immunofluorescence microscopy, and mutation analysis indicated that the N terminus of ezrin interacts with the C terminus of hamartin, whereas it interacts only weakly with merlin (607379) and not at all with giantin (602500). Hamartin also interacted with the N termini of radixin and moesin. Immunofluorescence microscopy showed that hamartin interacts with F-actin, suggesting that hamartin may be a direct binding partner for ERM proteins. Inactivation of hamartin by microscale chromophore-assisted laser inactivation (micro-CALI) or by antisense hamartin caused a marked retraction of the affected area of endothelial cell membranes, loss of adhesion, and cell rounding. Cell adhesion could be restored by injection of active RHO. Expression of hamartin in cells without organized actin filaments promoted the assembly of focal adhesions and the assembly of actin stress fibers. This activity required RHO and residues 145 to 510 of hamartin. Introduction of a C-terminal fragment of hamartin inhibited the assembly of actin stress fibers by lysophosphatidic acid, a serum factor that activates RHO, suggesting that the interaction of hamartin with ERM proteins is required upstream of RHO. Lamb et al. (2000) proposed that loss or perturbation of hamartin function leads to loss of adhesion to the cellular matrix and initiates the development of TSC hamartomas </p><p>Tapon et al. (2001) characterized mutations in the Drosophila Tsc1 and Tsc2 (gigas) genes. Inactivating mutations in either gene caused an identical phenotype characterized by enhanced growth and increased cell size with no change in ploidy. Overall, mutant cells spent less time in G1. Coexpression of both Tsc1 and Tsc2 restricted tissue growth and reduced cell size and cell proliferation. This phenotype was modulated by manipulations in cyclin levels. In postmitotic mutant cells, levels of cyclin E (123837) and cyclin A (123835) were elevated. This correlated with a tendency for these cells to reenter the cell cycle inappropriately, as is observed in the human lesions. </p><p>Potter et al. (2001) isolated a mutation in the Drosophila Tsc1 gene. Cells mutant for Tsc1 were dramatically increased in size yet differentiated normally. Organ size was also increased in tissues that contained a majority of mutant cells. Clones of Tsc1 mutant cells in the imaginal discs underwent additional divisions but retained normal ploidy. Potter et al. (2001) also showed that the Tsc1 protein binds to Drosophila Tsc2 in vitro. Overexpression of Tsc1 or Tsc2 alone in the wing and eye had no effect, but co-overexpression led to a decrease in cell size, cell number, and organ size. Genetic epistasis data were consistent with a model in which Tsc1 and Tsc2 function together in the insulin (INS; 176730) signaling pathway. </p><p>Inoki et al. (2002) showed that the Tsc1-Tsc2 complex inhibits the mammalian target of rapamycin (MTOR; 601231), leading to inhibition of p70 ribosomal S6 kinase-1 (608938) and activation of eukaryotic translation initiation factor 4E-binding protein-1 (EIF4EBP1; 602223). </p><p>Astrinidis et al. (2006) found that endogenous polo-like kinase-1 (PLK1; 602098) associated with the hamartin-tuberin complex in several human and nonhuman cell lines and that the complex localized to centrosomes. Phosphorylated hamartin interacted with PLK1 independent of tuberin, and the interaction required thr310 of hamartin. Hamartin negatively regulated the protein levels of PLK1 and regulated centrosome number in an MTOR-dependent manner. Hamartin-deficient mouse embryonic fibroblasts had an increased number of centrosomes and a mitotic defect leading to increased DNA content, and these defects were reversed by rapamycin. </p><p>Loss of the TSC genes leads to constitutive activation of MTOR and downstream signaling elements, resulting in tumor development, neurologic disorders, and severe insulin/IGF1 (147440) resistance. Ozcan et al. (2008) found that loss of TSC1 or TSC2 in cell lines and mouse or human tumors caused endoplasmic reticulum (ER) stress and activated the unfolded protein response. The resulting ER stress played a significant role in the MTOR-mediated negative feedback inhibition of insulin action and increased the vulnerability to apoptosis. </p><p>Choi et al. (2008) showed that Tsc1 and Tsc2 had critical functions in axon formation and growth in mouse. Overexpression of Tsc1/Tsc2 suppressed axon formation, whereas lack of Tsc1 or Tsc2 induced ectopic axons in vitro and in mouse brain. Tsc2 was phosphorylated and inhibited in axons, but not dendrites. Inactivation of Tsc1/Tsc2 promoted axonal growth, at least in part, via upregulation of neuronal polarity Sad kinase (see BRSK2; 609236), which was also elevated in cortical tubers of a TSC patient. Choi et al. (2008) concluded that TSC1 and TSC2 have critical roles in neuronal polarity, and that a common pathway regulates polarization and growth in neurons and cell size in other tissues. </p><p>To test for the role of intrinsic impediments to axon regrowth, Park et al. (2008) analyzed cell growth control genes using a virus-assisted in vivo conditional knockout approach. In wildtype adult mice, mTOR activity was suppressed and new protein synthesis was impaired in axotomized retinal ganglion cells, which may have contributed to the regeneration failure. Reactivating this pathway by conditional knockout of TSC1, a negative regulator of the mTOR pathway, led to axon regeneration. </p><p>DiBella et al. (2009) showed that morpholino knockdown of zebrafish Tsc1a led to a ciliary phenotype including kidney cyst formation and left-right asymmetry defects. Tsc1a localized to the Golgi, but morpholinos against it, nonetheless, acted synthetically with ciliary genes in producing kidney cysts. Consistent with a role of the cilium in the same pathway as Tsc genes, the TOR (FRAP1; 601231) pathway was found to be aberrantly activated in ciliary mutants, resembling the effect of Tsc1a knockdown. Kidney cyst formation in ciliary mutants was blocked by the Tor inhibitor rapamycin. DiBella et al. (2009) suggested a signaling network between the cilium and the TOR pathway wherein ciliary signals can feed into the TOR pathway and where Tsc1a may regulate the length of the cilium itself. </p><p>Hartman et al. (2009) reported that hamartin (TSC1) localized to the basal body of the primary cilium, and that Tsc1-null and Tsc2-null mouse embryonic fibroblasts (MEFs) were significantly more likely to contain a primary cilium than wildtype controls. In addition, the cilia of Tsc1- and Tsc2-null MEFs were 17 to 27% longer than cilia from wildtype MEFs. Enhanced ciliary formation in the Tsc1- and Tsc2-null MEFs was not abrogated by rapamycin, which suggests an mTOR-independent mechanism. Polycystin-1 (PC1; see 601313) has been found to interact with TSC2, but Pkd1-null MEFs did not have enhanced ciliary formation. While activation of mTOR has been observed in renal cysts from ADPKD patients, Pkd1-null MEFs did not have evidence of constitutive mTOR activation, thereby underscoring the independent functions of the TSC proteins and PC1 in regulation of primary cilia and mTOR. </p><p>Zhang et al. (2014) showed that as well as increasing protein synthesis, mTORC1 activation in mouse and human cells also promotes an increased capacity for protein degradation. Cells with activated mTORC1 exhibited elevated levels of intact and active proteasomes through a global increase in the expression of genes encoding proteasome subunits. The increase in proteasome gene expression, cellular proteasome content, and rates of protein turnover downstream of mTORC1 were all dependent on induction of the transcription factor NRF1 (NFE2L1; 163260). Genetic activation of mTORC1 through loss of the tuberous sclerosis complex tumor suppressors TSC1 or TSC2 (191092), or physiologic activation of mTORC1 in response to growth factors or feeding, resulted in increased NRF1 expression in cells and tissues. Zhang et al. (2014) found that this NRF1-dependent elevation in proteasome levels serves to increase the intracellular pool of amino acids, which thereby influences rates of new protein synthesis. The authors therefore concluded that mTORC1 signaling increases the efficiency of proteasome-mediated protein degradation for both quality control and as a mechanism to supply substrate for sustained protein synthesis. </p>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Tuberous Sclerosis</em></strong></p><p>
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Van Slegtenhorst et al. (1997) screened exons in the 1.4-Mb TSC1 region on chromosome 9 for mutations in tuberous sclerosis patients. One of the exons of the TSC1 gene screened for mutations demonstrated mobility shifts in heteroduplex analysis of samples from 10 of the 60 patient samples. Sequence analysis revealed 7 small frameshifting mutations (e.g., 605284.0001), 1 nonsense mutation (605284.0002), 1 missense mutation (605284.0003), and 1 polymorphism that did not change the encoded amino acid. It was exon 15 in which the high frequency of mutations was found on the initial screen. Exon 15 is 559 bp long and represents 16% of the coding region. Mutation was found in exon 15 in 8 of 55 tuberous sclerosis families (15%) showing linkage to 9q34 and in only 15 of 607 (2.5%) of sporadic patients or families uninformative for linkage. A screen for mutations in all coding exons in 20 familial cases and 152 sporadic patients yielded 8 mutations in each group (40% and 5%, respectively). Of 32 distinct mutations found in TSC1, 30 were truncating, and 1 mutation (2105delAAAG; 605284.0001) was seen in 6 apparently unrelated patients. In one of these 6, a somatic mutation in the wildtype allele was found in a tuberous sclerosis-associated renal carcinoma, which suggested that hamartin acts as a tumor suppressor. </p><p>Jones et al. (1997) comprehensively defined the TSC1 mutation spectrum in 171 sequentially ascertained, unrelated TSC patients by SSCP and heteroduplex analysis of all 21 coding exons, and by assaying a restriction fragment spanning the whole locus. Mutations were identified in 9 of 24 familial cases, but in only 13 of 147 sporadic cases. In contrast, a limited screen revealed mutations in the TSC2 gene in 2 of the 24 familial cases and in 45 of the 147 sporadic cases. Thus, TSC1 mutations were significantly underrepresented among sporadic cases. Both large deletions and missense mutations were common at the TSC2 locus, whereas most TSC1 mutations were small truncated lesions. Mental retardation was significantly less frequent among carriers of TSC1 mutations than TSC2 mutations (odds ratio, 5.54 for sporadic cases only; 6.78 +/- 1.54 when a single randomly selected patient per multigeneration family was also included). No correlation between mental retardation and the type of mutation was found. Jones et al. (1997) concluded that there is a reduced risk of mental retardation in tuberous sclerosis-1 as opposed to tuberous sclerosis-2 and that consequent ascertainment bias, at least in part, explains the relative paucity of TSC1 mutations in sporadic TSC. </p><p>Kwiatkowska et al. (1998) performed a comprehensive analysis for mutations in the TSC1 gene using Southern blot analysis, and SSCP and heteroduplex analysis of amplified exons in 13 families with genetic linkage to the TSC1 region, 22 small families without linkage information, and 126 sporadic patients. Seventeen unique mutations were identified in 21 patients. Mutations were found in 7 of 13 (54%) tuberous sclerosis-1-linked families, in 1 of 22 (5%) small families without linkage, and in 13 of 126 (10%) sporadic cases. The mutations were all chain-terminating, with 14 small deletions, 1 small insertion, and 6 nonsense mutations. Twelve of the 21 mutations were previously reported by van Slegtenhorst et al. (1997), and 9 were new. In families with mutations, all individuals carrying a mutation met formal diagnostic criteria for tuberous sclerosis, apart from a 3-year-old girl who had inherited a deletion mutation and who had no seizures, normal intelligence, normal abdominal ultrasound, and hypomelanotic macules only on physical examination. Her 7-year-old sister with the same TSC1 mutation had severe mental retardation. They found no significant difference in the incidence and severity of mental retardation in the 13 sporadic patients with TSC1 mutations versus the entire sporadic cohort. The observation indicated that TSC1 mutations are all inactivating, suggested that tuberous sclerosis-1 occurs in only 15 to 20% of the sporadic tuberous sclerosis population, and demonstrated that presymptomatic tuberous sclerosis occurs. </p><p>Jones et al. (1999) reported a comprehensive mutation analysis of the TSC1 and TSC2 genes in a cohort of 150 unrelated tuberous sclerosis patients and their families, using heteroduplex and SSCP analysis of all coding exons, and pulsed field gel electrophoresis, Southern blot analysis, and long PCR to screen for large rearrangements. Mutations were detected in 120 (80%) of the 150 cases, affecting the TSC1 gene in 22 cases and the TSC2 gene in 98 cases. TSC1 mutations were significantly underrepresented in sporadic cases. All TSC1 mutations were predicted to be truncating, consistent with a structural or adaptor role for the encoded protein. In contrast, 22 patients had TSC2 missense mutations that were found predominantly in the GAP-related domain (8 cases) and in a small region encoded in exons 16 and 17, between nucleotides 1849 and 1859 (8 cases), consistent with the presence of residues performing key functions at these sites. Intellectual disability was significantly more frequent in tuberous sclerosis-2 sporadic cases than in tuberous sclerosis-1 sporadic cases. </p><p>Young et al. (1998) performed a mutation screen of the TSC1 gene in a panel of 79 tuberous sclerosis patients. Twelve of the patients were from families showing linkage to 9q34 markers. Causative mutations in the TSC1 gene were found in 27 of these patients, and 5 other variations in the gene were identified. Twenty-six of the mutations were predicted to cause premature termination of the protein product of the gene and one mutation was in a splice site. The mutation screen showed that TSC1 mutations are rarer in sporadic tuberous sclerosis patients than in familial cases. This is consistent with the expectation that a larger proportion of the tuberous sclerosis-2 patients will be sporadic because of the more severe nature of TSC2 as compared to TSC1. Young et al. (1998) found that in family 214 of Povey et al. (1994) a presumably nonpenetrant mother of a severely affected boy in one branch of the family did not carry the nonsense mutation leu250-to-ter present in affected individuals in other branches of the family. Furthermore, the grandmother of the severely affected boy was the 'connecting link' to the rest of the family not carrying the mutation, thus leading to the conclusion that the single ungual fibroma that had been thought to mean that she was affected was not in fact diagnostic of tuberous sclerosis. </p><p>Ali et al. (1998) screened 83 unrelated individuals with tuberous sclerosis for mutations in TSC1. Mutations were found in 16 of the 83 cases (19%). The mutations comprised base substitutions, small insertions, or small deletions giving rise to 6 nonsense mutations, 8 frameshifts, and 2 splice site mutations, all of which would be expected to result in a truncated or absent protein. In 8 of 10 cases showing linkage to the TSC1 locus, mutations were found. In the remaining 73 unassigned cases, only 8 mutations were found (11%). From these data, Ali et al. (1998) estimated that TSC1 mutations account for 22% of tuberous sclerosis cases. </p><p>Mayer et al. (1999) pointed out that all known TSC1 mutations, as well as most TSC2 mutations, truncate the proteins hamartin and tuberin, respectively. Mayer et al. (1999) described an RNA-based screening of the entire coding regions of both TSC genes for truncating mutations, applying the protein truncation test (PTT). Simultaneous investigation of both TSC genes in a group of 48 unassigned TSC patients, which were previously tested to exclude large intragenic TSC2 rearrangements, revealed aberrant migrating polypeptides resulting from truncating mutations in 9 TSC1 cases and in 16 TSC2 cases, while 3 TSC2 cases showed enlarged proteins. TSC1 mutations included 2 nonsense mutations, 4 insertions, and 3 splice mutations. Nineteen mutations identified in TSC2 comprised 4 different nonsense mutations in 5 patients, 1 deletion, 1 insertion, and 7 different splicing aberrations due to at least 8 different mutations found in 12 patients. Additional predicted truncating mutations according to PTT without possible identification of the causative alteration allowed assignment to TSC1 in 1 and TSC2 in 7 cases. Twelve patients without abnormalities in the PTT were assumed to harbor missense mutations, probably in TSC2. The high proportion of TSC2 splicing aberrations strengthens the importance of intronic disease-causing mutations and the application of RNA-based screening methods to confirm their consequences. Benit et al. (1999) likewise devised a protein truncation test to analyze the full-length coding sequence of TSC1. In a study of 15 cases (12 sporadic and 3 familial) by a combination of PTT and SSCP, they found 5 of 15 mutations, whereas PTT alone detected 4 of 15 truncating mutations, 2 of which escaped SSCP analysis. </p><p>Niida et al. (1999) reported mutation analysis of the entire coding region of the TSC1 and TSC2 genes in 126 unrelated TSC patients, including 40 familial and 86 sporadic cases, by SSCP followed by direct sequencing. Mutations were identified in a total of 74 (59%) cases, including 16 TSC1 mutations (5 sporadic and 11 familial) and 58 TSC2 mutations (42 sporadic and 16 familial). Overall, significantly more TSC2 mutations were found in this population, with a relatively equal distribution of mutations between TSC1 and TSC2 among the familial cases, but a marked underrepresentation of TSC1 mutations among the sporadic cases (p = 0.0035, Fisher exact test). All TSC1 mutations were predicted to be protein truncating; however, in TSC2 13 missense mutations were found, 5 clustering in the GAP-related domain and 3 others occurring in exon 16. Upon comparison of clinical manifestations, including the incidence of intellectual disability, they could not find any observable differences between TSC1 and TSC2 patients. </p><p>Carbonara et al. (1996) studied LOH in both the TSC1 and TSC2 loci and 7 tumor suppressor gene-containing regions, p53 (191170), NF1 (613113), NF2 (607379), BRCA1 (113705), APC (611731), VHL (608537), and MLM (155600), in 20 hamartomas from 18 tuberous sclerosis patients. Overall, 8 angiomyolipomas, 8 giant cell astrocytomas, 1 cortical tuber, and 3 rhabdomyomas were analyzed. LOH at either TSC locus was found in a large fraction of the informative patients, both sporadic (7/14) and familial (1/4). A statistically significant preponderance of LOH of TSC2 was observed in the sporadic group (P less than 0.01). Carbonara et al. (1996) suspected that bias in the selection for TSC patients with the most severe organ impairment was responsible for the finding. According to this suggestion, a TSC2 defect may confer a greater risk for early kidney failure or possibly a more rapid growth of a giant cell astrocytoma. None of the 7 antioncogenes tested showed LOH, indicating that the loss of either TSC gene product may be sufficient to promote hamartomatous cell growth. The observation of LOH at different markers in an astrocytoma and in an angiomyolipoma from the same patients suggested to the authors the multifocal origin of a second-hit mutation. </p><p>Van Slegtenhorst et al. (1999) reported mutation analysis of the TSC1 gene in a cohort of 225 unrelated patients. Of 29 mutations detected, all were small changes leading to a truncated protein except for a splice site mutation and 2 in-frame deletions in exons 7 and 15. No clear difference was observed in the clinical phenotype of patients with an in-frame deletion or a frameshift or nonsense mutation. Van Slegtenhorst et al. (1999) found no obvious underrepresentation of mutations among sporadic cases, in contrast to the findings of Jones et al. (1999). Van Slegtenhorst et al. (1999) found no genotype-phenotype correlation for patients with TSC1 mutations compared to the overall population of tuberous sclerosis patients. </p><p>Yamashita et al. (2000) examined 27 unrelated Japanese patients with tuberous sclerosis for mutations in the TSC1 and TSC2 genes, using SSCP analysis of genomic DNA. They identified 4 mutations in TSC1 that they considered to be pathogenic, including 3 frameshifts and 1 nonsense mutation. All were expected to result in a truncated hamartin gene product. The authors found no difference in the risk for mental retardation between their series of tuberous sclerosis-1 and tuberous sclerosis-2 patients. In addition, the extent of protein truncation expected from the mutations did not correlate with the severity of clinical symptoms. </p><p>Carbonara et al. (1994) presented evidence of loss of heterozygosity (LOH) at the tuberous sclerosis-1 critical region in a giant cell astrocytoma occurring in a patient with familial tuberous sclerosis. Segregation analysis showed that the 9q34 haplotype lost in the tumor carried the putative normal TSC1 gene. These data supported the hypothesis of both a germline and somatic loss-of-function mutation necessary for the development of tuberous sclerosis hamartomas and suggested a tumor-suppressor activity for the TSC1 gene product. (In the same astrocytoma, a second small region of LOH was found at 9p21.) Green et al. (1994) likewise found allele loss consistent with a tumor-suppressor role of the TSC1 gene. They studied 6 hamartomas from 4 sporadic and 2 familial cases of tuberous sclerosis, none of which showed allele loss for markers on 16p13.3. The hamartomas were paraffin-embedded sections of 3 renal angiomyolipomas, 2 giant cell astrocytomas, and a cardiac rhabdomyoma. One angiomyolipoma showed allele loss for the markers ABO, DBH, and D9S66. The family structure did not permit determination of the phase of the disease and marker alleles. Findings supported the assignment of tuberous sclerosis-1 to 9q34 and placed the gene between D9S149 and D9S67. Similar evidence had supported a growth suppressor role for the TSC2 gene. </p><p>Green et al. (1996) used nonrandom X chromosome inactivation studies to demonstrate the clonality of tuberous sclerosis hamartomas. Previously, LOH for DNA markers in the region of either the TSC1 gene on 9q34 or the TSC2 gene on 16p13.3 had supported the conclusion that these lesions are indeed clonal. In the studies of X-chromosome inactivation, Green et al. (1996) examined clonality in 13 TSC hamartomas from female cases by analyzing X-chromosome inactivation in DNA extracted from archival paraffin-embedded tumors compared with normal tissue from the same patient. Seven of the cases were sporadic; 2 were from families linked to 9q34, 1 was from a family linked to 16p13.3 and 3 were from families too small to assign by linkage. Only 4 of the 13 hamartomas had previously shown LOH, 1 in the region of the TSC1 gene and 3 in the region of the TSC2 gene. A PCR assay was used to analyze differential methylation of the HpaII restriction site adjacent to the androgen-receptor triplet-repeat polymorphism on Xq11-q12. In 12 of the lesions, there was a skewed inactivation pattern, one X-chromosome being fully methylated and the other unmethylated. Normal tissue showed a random pattern of inactivation. The finding was considered particularly intriguing by the authors since the lesions were composed of more than 1 cell type. </p><p>Henske et al. (1996) analyzed 87 lesions from 47 TSC patients for LOH in the TSC1 and TSC2 regions. Of the 28 patients with angiomyolipomas or rhabdomyomas, LOH for 16p13 was detected in lesions from 12 (57%). LOH for 9q34 was detected in only 1 patient. The authors noted that LOH occurred in only 4% of TSC brain lesions and suggested that TSC brain lesions may result from a different pathogenetic mechanism than TSC kidney or rhabdomyoma lesions. </p><p>Niida et al. (2001) analyzed 24 hamartomas from 10 patients for second-hit mutations by multiple methods including LOH analysis, SSCP screening of TSC1 and TSC2, promoter methylation studies of TSC2, and clonality analysis. The results provided evidence that complete inactivation of the TSC genes is characteristic of renal angiomyolipomas but not of other TSC lesions. </p><p>Sepp et al. (1996) described the spectrum of LOH in 51 hamartomas from 34 cases of tuberous sclerosis. Of 51 hamartomas analyzed, 21 (41%) showed LOH; 16 hamartomas showed LOH around TSC2 and 5 showed LOH in the vicinity of TSC1. No hamartomas showed LOH for markers around both loci. Sepp et al. (1996) reported that there did not appear to be any major differences in the frequency of LOH between the different types of hamartoma. LOH was observed in 7 of 17 angiomyolipomas, 5 of 9 giant cell astrocytomas, 3 of 8 fibromas, 3 of 5 cortical tubers, and in a shagreen patch, a cardiac rhabdomyoma, and a renal carcinoma. Sepp et al. (1996) noted that the excess of LOH for the TSC2 region on chromosome 16p13.3 may simply reflect that the TSC1 locus is less well defined and that LOH for 9q34 is therefore harder to find. </p><p>Bjornsson et al. (1996) studied 6 TSC-associated RCCs. Their findings suggested that some TSC-associated RCCs have clinical, pathologic, and genetic features which distinguish them from sporadic RCC. Clinically the TSC-associated RCC occurred at a younger age (36 years) than sporadic tumors and occurred primarily in women (5 of 6 cases). Bjornsson et al. (1996) reported that 5 tumors displayed clear cell morphology and 2 of those 5 had high-grade spindle cell areas in addition to granular cell histology. Of the 6 patients studied, 4 died from their carcinoma and 3 had pulmonary metastases in addition to retroperitoneal spread. The 2 surviving patients had tumors that were detected incidentally (one at surgery for angiomyolipoma and renal hemorrhage, the other at surgery for renal cysts). Immunostaining for a melanocyte-associated marker, HMB-45, was positive in 4 of the 6 cases. LOH was observed on 9q34, 16p13.3, and in 2 cases on chromosome 3p. Bjornsson et al. (1996) noted that the tumor with LOH of 9q34 alone was incidentally detected and lacked anaplastic features. In contrast, the tumors with LOH on 9q34 and 3p had anaplastic features and metastasized. </p><p>Cheadle et al. (2000) reviewed the molecular genetic advances in tuberous sclerosis. They found reports of 154 cases with mutations in the TSC1 gene and 292 cases with mutations in the TSC2 gene. Forty-seven percent (73/154) of TSC1 mutations were single-base substitutions, 82% of which were nonsense mutations. </p><p>In a study of 224 index patients with tuberous sclerosis, Dabora et al. (2001) found mutations in 186 (83%), comprising 138 small TSC2 mutations, 20 large TSC2 mutations, and 28 small TSC1 mutations. Clinical assessment indicated that sporadic patients with TSC1 mutations had, on average, milder disease than did patients with TSC2 mutations, despite being of similar age. They had a lower frequency of seizures and moderate to severe mental retardation, fewer subependymal nodules and cortical tubers, less severe kidney involvement, no retinal hamartomas, and less severe facial angiofibroma. Patients in whom no mutation was found also had disease that was milder, on average, than that in patients with TSC2 mutations. Although there was overlap in the spectrum of many clinical features of patients with TSC1 versus TSC2 mutations, some features (grade 2-4 kidney cysts or angiomyolipomas, forehead plaques, retinal hamartomas, and liver angiomyolipomas) were very rare or not seen at all in TSC1 patients. Thus, both germline and somatic mutations appear to be less common in TSC1 than in TSC2. The reduced severity of disease in patients without defined mutations suggests that many of these patients are mosaic for a TSC2 mutation and/or have TSC because of mutations in an as yet undefined locus with a relatively mild clinical phenotype. </p><p>Langkau et al. (2002) genotyped 68 unrelated and nonselected patients (59 sporadic and 9 familial) with clinically confirmed TSC and identified 29 mutations in the TSC2 gene and 2 mutations in the TSC1 gene. They noted that the TSC1-TSC2 mutation ratio in this group of patients differed significantly from the 1:1 ratio previously predicted on the basis of linkage studies. They suggested that milder phenotypes are more often associated with TSC1 mutations and are likely to escape ascertainment. </p><p>Many mRNAs carrying mutations that encode a truncated protein are subject to nonsense-mediated mRNA decay (NMD), which results in reduced levels of mutant transcript. Virtually all TSC1 mutations truncate the protein product. Jeganathan et al. (2002) used coding and 3-prime untranslated region polymorphisms in TSC1 to develop a transcript imbalance assay to investigate TSC1 transcript levels in patients. This approach allowed the correct identification of 6 of 7 TSC1 patients tested blind from a panel of TSC1 and TSC2 patients, with no false positives. The extent of NMD in TSC1 correlated with each individual mutation regardless of intrafamilial variation in clinical features and with no strong evidence for positional bias. </p><p>Au et al. (2007) performed mutational analyses on 325 individuals with definite tuberous sclerosis complex diagnostic status. The authors identified mutations in 72% (199 of 257) of de novo and 77% (53 of 68) of familial cases, with 17% of mutations in the TSC1 gene and 50% in the TSC2 gene. There were 4% unclassified variants and 29% with no mutation identified. Genotype/phenotype analyses of all observed tuberous sclerosis complex findings in probands were performed, including several clinical features not analyzed in 2 previous large studies (see, e.g., Sancak et al., 2005). Au et al. (2007) showed that patients with TSC2 mutations have significantly more hypomelanotic macules and learning disability in contrast to those with TSC1 mutations, findings not noted in previous studies. The authors also observed results consistent with 2 similar studies suggesting that individuals with mutations in TSC2 have more severe symptoms. </p><p>Nellist et al. (2009) identified 8 different missense mutations in the TSC1 gene (see, e.g., M224R; 605284.0008 and L180P; 605284.0009) that segregated with tuberous sclerosis. In vitro functional expression studies demonstrated that these changes resulted in reduced levels of TSC1 and a reduction in TSC1-dependent inhibition of mTOR activity, as detected by immunoblotting. In each case, the functional characterization was consistent with the genetic and phenotypic findings, indicating that the missense changes were pathogenic. Nellist et al. (2009) concluded that mutations close to the N terminus of TSC1 (amino acids 117 to 224) reduce the steady-state levels of TSC1. </p><p><strong><em>Pulmonary Lymphangioleiomyomatosis</em></strong></p><p>
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Pulmonary lymphangioleiomyomatosis (LAM; 606690) is a destructive lung disease characterized by a diffuse hamartomatous proliferation of smooth muscle cells in the lungs. Pulmonary LAM can occur as an isolated form (sporadic LAM) or in association with tuberous sclerosis complex (TSC-LAM). Sato et al. (2002) studied the TSC1 and TSC2 genes in 6 Japanese patients with TSC-LAM and 22 patients with sporadic LAM and identified 6 novel mutations. TSC2 germline mutations were detected in 2 (33.3%) of the 6 patients with TSC-LAM, and a TSC1 germline mutation was detected in 1 (4.5%) of the 22 sporadic LAM patients. In accordance with the tumor suppressor model, LOH was detected in LAM cells from 3 of 4 patients with TSC-LAM and from 4 of 8 patients with sporadic LAM. Furthermore, an identical LOH or 2 identical somatic mutations were demonstrated in LAM cells microdissected from several tissues, suggesting that LAM cells can spread from one lesion to another. These results confirmed the prevailing concept of pathogenesis of LAM: TSC-LAM has a germline mutation, but sporadic LAM does not; sporadic LAM is a TSC2 disease with 2 somatic mutations; and a variety of TSC mutations can cause LAM. However, this study indicated that a fraction of sporadic LAM can be a TSC1 disease; therefore, both TSC genes should be examined, even in patients with sporadic LAM. </p><p><strong><em>Focal Cortical Dysplasia, Type II, Somatic</em></strong></p><p>
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Focal cortical dysplasia type II (FCORD2; 607341) is characterized by a localized malformation of the neocortex and underlying white matter. Balloon cells, similar to those observed in TSC, are present in many cases, referred to by Becker et al. (2002) as FCD(bc). Becker et al. (2002) studied alterations of the TSC1 and TSC2 genes in a cohort of 48 patients with chronic, focal epilepsy and histologically documented FCD(bc). DNA was obtained after microdissection and laser-assisted isolation of balloon cells, dysplastic neurons, and nonlesional cells from adjacent normal brain tissue. Sequence alterations resulting in amino acid exchange of the TSC1 gene product affecting exons 5 and 17 and silent base exchanges in exons 14 and 22 were increased in patients with FCD(bc) compared with 200 controls. Sequence alterations were detected in FCD(bc) and adjacent normal cells. In 24 patients, DNA was suitable to study LOH at the TSC1 gene locus in microdissected FCD(bc) samples compared with control tissues. LOH was found in 11 FCD(bc) cases. In the TSC2 gene, only silent polymorphisms were detected at similar frequencies as in controls. Becker et al. (2002) concluded that FCD(bc) constitutes a clinicopathologic entity with distinct neuroradiologic, neuropathologic, and molecular genetic features, and suggested the TSC1 gene has a role in its development, with a pathogenic relationship between it and the TSC complex. </p><p>Becker et al. (2002) noted that LOH for alleles at 16p13.3 (where the TSC2 gene is located) has been observed in brain lesions of TSC, and at 9q34 (where the TSC1 gene is located) in extracerebral lesions of TSC. Their findings of LOH related to the TSC1 gene in focal cortical dysplasia are possibly relevant to the 2-hit hypothesis for the inactivation of tumor suppressor genes. The observed combination of LOH within the TSC1 locus and sequence polymorphism in the other alleles suggests that the latter functions as a predisposing germline variant with low penetrance and a severely restricted manifestation pattern. Given that TSC1 and TSC2 may act as a cell cycle-regulating complex (Potter et al., 2001; Tapon et al., 2001), such variant alleles may induce proliferation activity for a limited time during brain development. </p><p>In a detailed genotype-phenotype analysis of 33 patients with focal cortical dysplasia, including 23 with FCD type II, Gumbinger et al. (2009) identified several sequence variations in the TSC1 and TSC2 genes in both lesional brain tissue and blood of the patients, but in similar frequencies to that of the normal population. Most of the sequence alterations were silent. Gumbinger et al. (2009) concluded that focal cortical dysplasia is not caused by mutation in the TSC genes and does not appear to be promoted by TSC polymorphisms. </p><p>In brain tissue resected from 4 unrelated children with seizures due to FCD type II (FCORD2; 607341), including 3 with type IIa and 1 with type IIb, Lim et al. (2017) identified de novo somatic missense mutations in the TSC1 gene (R22W, 605284.0010 and R204C, 605284.0011). The mutations, which were found by targeted sequencing of genes in the MTOR pathway, showed very low frequency in brain tissue, less than 3%. The patients were part of a cohort of 40 individuals with FCD type II whose brain tissue was negative for somatic mTOR mutations. Patient dystrophic brain cells and TSC1 mutant-transfected cells showed increased S6K phosphorylation (RPS6KB1; 608938) compared to wildtype, consistent with hyperactivation of the mTOR pathway. Mutant TSC1 also showed impaired binding to TSC2, indicating disruption of the TSC1-TSC2 complex. Abnormal S6K phosphorylation in transfected cells was inhibited by treatment with rapamycin. </p><p><strong><em>Everolimus Sensitivity</em></strong></p><p>
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Iyer et al. (2012) studied the tumor genome of a patient with metastatic bladder cancer who achieved a durable (greater than 2 years) and ongoing complete response to everolimus, a drug targeting the mTORC1 complex (see 601231). Iyer et al. (2012) identified a 2-bp deletion in the TSC1 gene resulting in a frameshift truncation, and a nonsense mutation in the NF2 (607379) gene. Iyer et al. (2012) sequenced both genes in the second cohort of 96 high-grade bladder cancers and identified 5 additional somatic TSC1 mutations, whereas no additional NF2 mutations were detected. Subsequently, Iyer et al. (2012) explored whether TSC1 mutations is a biomarker of clinical benefit from everolimus therapy in bladder cancer, and studied 13 additional bladder cancer patients treated with everolimus. Three additional tumors harbored nonsense mutations in TSC1, including 2 patients who had minor responses to everolimus (17 and 24% tumor regression, respectively). Tumors from 8 of the 9 patients who showed disease progression were TSC1 wildtype. Patients with TSC1-mutant tumors remained on everolimus longer than those with wildtype tumors (7.7 vs 2.0 months, p = 0.004) with a significant improvement in time to recurrence (4.1 vs 1.8 months; hazard ratio = 18.5, 95% confidence interval 2.1 to 162, p = 0.001). Iyer et al. (2012) concluded that mTORC1-directed therapies may be most effective in cancer patients whose tumors harbor TSC1 somatic mutations. </p>
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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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<p>Kobayashi et al. (2001) established a line of Tsc1 knockout mice by gene targeting. Heterozygous mutant mice (Tsc1 +/-) developed renal and extrarenal tumors such as hepatic hemangiomas. In these tumors, loss of the wildtype Tsc1 allele was observed. Homozygous Tsc1 mutants died around embryonic days 10.5 to 11.5, frequently associated with neural tube unclosure. As a whole, phenotypes of Tsc1-KO mice resembled those of Tsc2-KO mice previously reported, suggesting that the presumptive common pathway for the Tsc1 and Tsc2 products may exist in mice as is thought to be the case in humans. Notably, however, development of renal tumors in Tsc1 +/- mice was apparently slower than that in Tsc2 +/- mice. </p><p>Kwiatkowski et al. (2002) developed a murine model of TSC1 disease wherein the mutant allele lacked exons 17 and 18, which leads to premature termination. Tsc1-null embryos died at midgestation from a failure of liver development. Tsc1 heterozygotes developed kidney cystadenomas and liver hemangiomas at high frequency, but the incidence of kidney tumors was somewhat lower than in Tsc2 heterozygous mice. Liver hemangiomas were more common, more severe, and caused higher mortality in female than in male Tsc1 heterozygotes. Tsc1-null embryo fibroblast lines exhibited persistent phosphorylation of the p70-S6K and its substrate S6, which was sensitive to treatment with rapamycin, indicating constitutive activation of the MTOR-S6K pathway due to loss of the Tsc1 protein, hamartin. Hyperphosphorylation of S6 was also seen in kidney tumors in the heterozygous mice, suggesting that inhibition of this pathway may aid in control of TSC hamartomas. </p><p>Uhlmann et al. (2002) demonstrated that heterozygous Tsc1 and Tsc2 mice exhibit increased numbers of astrocytes, suggesting that hamartin and tuberin are important growth regulators for astrocytes. To study the consequence of hamartin loss on astrocyte function, Uhlmann et al. (2002) generated mice in which the Tsc1 gene was specifically inactivated in astrocytes. The mice demonstrated an age-dependent progression of increased astrocyte proliferation, abnormal neuronal organization in the hippocampus, seizures, and death. The findings suggested that the increase in astrocyte proliferation preceded the neuronal abnormalities, causing mass effect changes or disturbance of complex astrocyte-neuron interactions. In culture, the Tsc1-null astrocytes grew in association with reduced expression of the cell cycle regulator p27(KIP1) (600778), suggesting disruption of a TSC-mediated growth regulation complex involving p27(KIP1). </p><p>Meikle et al. (2005) developed a conditional mouse mutant of Tsc1. Mice with ventricular loss of Tsc1 had a median survival of 6 months and developed a dilated cardiomyopathy with the occurrence of scattered foci of enlarged ventricular myocytes. The enlarged cells were PAS-positive, indicating the presence of excess glycogen, and expressed elevated levels of phospho-S6 (RPS6; 180460), similar to findings in patient rhabdomyoma cells. The observations were consistent with a 2-hit mechanism for rhabdomyoma formation. However, the mice showed no evidence of fetal/neonatal demise, and there was no evidence of proliferation in the lesions. Meikle et al. (2005) proposed that these differences may be due to the timing of loss of Tsc1 in the ventricular myocytes and/or the truncated gestational period in the mouse compared with humans. </p><p>Wilson et al. (2005) showed that approximately 27% of Tsc1 +/- mice on a C57BL/6 background died at 1 to 2 days from unknown causes. Forty-four percent of Tsc1 +/- mice on a C3H background developed macroscopically visible renal lesions as early as 3 to 6 months, increasing to 95% by 15 to 18 months. Renal lesions progressed from cysts through cystadenomas to solid carcinomas. Eighty percent of Tsc1 +/- mice on a Balb/c background exhibited solid renal cell carcinomas by 15 to 18 months, and lesions showed loss of the wildtype Tsc1 allele and elevated protein levels of MTOR and RPS6. </p><p>Goorden et al. (2007) found that Tsc1 +/- mice had no spontaneous seizures or cerebral lesions but showed impaired learning in hippocampus-sensitive versions of learning tasks and impaired social behavior. The findings indicated that haploinsufficiency for Tsc1 resulted in a functional neuronal deficit in the absence of overt cerebral pathology. </p><p>Zeng et al. (2008) observed that mice with conditional Tsc1 inactivation primarily in glia developed glial proliferation, enlarged brain size, progressive epilepsy, and premature death. Treatment with rapamycin at postnatal day 14 before the onset of neurologic symptoms prevented the development of epilepsy and premature death. Treatment at 6 weeks, after the onset of symptoms, suppressed seizures and prolonged survival. Brain histology showed that treatment with rapamycin resulted in decreased abnormal astrocyte proliferation and increased neuronal organization compared to untreated mice, even at later treatment. Rapamycin caused a dose-dependent decrease in S6 phosphorylation, indicating inhibition of the MTOR pathway. Cessation of rapamycin treatment resulted in reappearance of seizures, progressive brain enlargement, and premature death, similar to untreated mice. Zeng et al. (2008) concluded that rapamycin has strong efficacy for preventing seizures and prolonging survival in these transgenic mice. </p><p>Independently, Abs et al. (2013) found that induced deletion of Tsc1 in adult mice resulted in activation of the MTOR complex-1 (TORC1) pathway and epilepsy. Prior to seizure onset, mutant mice showed enhanced neuronal excitability and decreased threshold for long-term potentiation. Rapamycin treatment reduced TORC1 activity and abolished seizures. </p><p>Patients with tuberous sclerosis often develop renal cysts and those with inherited codeletions of PKD1 gene (601313) develop severe, early-onset polycystic kidneys. Using mouse models, Bonnet et al. (2009) showed that many of the earliest lesions from Tsc1 +/-, Tsc2 +/-, and Pkd1 +/- mice did not exhibit activation of mTOR (601231), confirming an mTOR-independent pathway of renal cystogenesis. Using Tsc1/Pkd1 and Tsc2/Pkd1 heterozygous double-mutants, the authors showed functional cooperation and an effect on renal primary cilium length between hamartin and tuberin with polycystin-1. The Tsc1, Tsc2, and Pkd1 gene products helped regulate primary cilia length in renal tubules, renal epithelial cells, and precystic hepatic cholangiocytes. Consistent with the function of cilia in modulating cell polarity, Bonnet et al. (2009) found that many dividing precystic renal tubule and hepatic bile duct cells from Tsc1, Tsc2, and Pkd1 heterozygous mice were highly misoriented. Bonnet et al. (2009) proposed that defects in cell polarity may underlie cystic disease associated with TSC1, TSC2, and PKD1, and that targeting of this pathway may be of key therapeutic benefit. </p><p>Zhou et al. (2009) developed a polycystic kidney disease (PKD) mouse model by knocking out Tsc1 in a subset of renal tubular cells. Extensive renal cyst formation in these mice was accompanied by broadly elevated mammalian target of rapamycin complex-1 (mTORC1; 607536) activity in both cell-autonomous and non-cell-autonomous compartments. Cyst development required mTORC1 activation, as low dosage of rapamycin administration effectively blocked cyst formation. Disruption of Pten (601728), an upstream regulator of Tsc1/Tsc2, in the same cells did not lead to PKD, seemingly due to limited activation of mTORC1, suggesting to the authors that PTEN may not be a major upstream regulator of TSC/mTORC1 during early postnatal kidney development. </p><p>In mutant mice lacking the Tsc1 gene in oocytes, Adhikari et al. (2010) showed that the entire pool of primordial follicles was activated prematurely due to elevated mTORC1 activity in the oocyte, resulting in follicular depletion in early adulthood and premature ovarian failure (POF). Maintenance of the quiescence of primordial follicles required synergistic, collaborative functioning of both Tsc1 and Pten, and these 2 molecules suppressed follicular activation through distinct ways. Adhikari et al. (2010) concluded that Tsc/mTORC1 signaling and PTEN/PI3K (see 171834) signaling synergistically regulate the dormancy and activation of primordial follicles, and together ensure the proper length of female reproductive life. </p><p>Tsai et al. (2012) showed that both heterozygous and homozygous loss of Tsc1 in mouse cerebellar Purkinje cells results in autistic-like behaviors, including abnormal social interaction, repetitive behavior, and vocalizations, in addition to decreased Purkinje cell excitability. Treatment of mutant mice with the mTOR inhibitor rapamycin prevented the pathologic and behavioral deficits. Tsai et al. (2012) concluded that their findings demonstrated new roles for Tsc1 in Purkinje cell function and defined a molecular basis for a cerebellar contribution to cognitive disorders such as autism. </p><p>Lim et al. (2017) demonstrated that knockdown of the Tsc1 gene in developing mouse neurons, using the CRISPR/CASP9 somatic genome editing method in utero, resulted in abnormal neuronal phenotypes resembling focal cortical dysplasia type II in humans, hyperactivation of the mTOR pathway, and epileptic seizures in mice. There was also evidence of abnormal radial migration of cortical neurons in CRISPR-treated neurons. </p><p>Ercan et al. (2017) found that loss of Tsc1/Tsc2 in mouse neurons resulted in a block in oligodendrocyte development in vitro and in oligodendrocyte hypomyelination in vivo. These processes were mediated by neuronal Ctgf (121009), which was highly expressed and secreted from Tsc-deficient neurons and blocked development of oligodendrocytes. Expression of Srf (600589), the transcriptional regulator of Ctgf, was also decreased in Tsc-deficient neurons. Myelination could be improved by genetic ablation of Ctgf in neurons lacking Tsc1. Electron microscopy analysis suggested that this rescue of myelination was caused by the rescue of myelinated axon numbers, rather than changes in myelin thickness. </p>
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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>11 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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<h4>
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<span class="mim-font">
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<strong>.0001 TUBEROUS SCLEROSIS 1</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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TSC1, 4-BP DEL, 2105AAAG
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ClinVar: RCV000005403, RCV000042099, RCV000189868
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</span>
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<span class="mim-text-font">
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<p>Van Slegtenhorst et al. (1997) found a 4-bp deletion in exon 15 of the TSC1 gene (2105delAAAG) in 6 apparently unrelated individuals with tuberous sclerosis (191100). Four were familial and 2 were sporadic. In 2 familial cases with the deletion and a sporadic case, haplotype analysis using flanking markers confirmed an independent origin of the 3 mutations. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 TUBEROUS SCLEROSIS 1</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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TSC1, LEU250TER
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<br />
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SNP: rs118203447,
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ClinVar: RCV000005404, RCV000042356
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</span>
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<span class="mim-text-font">
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<p>In a patient with tuberous sclerosis-1 (191100), van Slegtenhorst et al. (1997) identified a nonsense mutation in the TSC1 gene, a T-to-G transversion of nucleotide 970 leading to termination at amino acid 250. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</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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TSC1, LYS587ARG
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<br />
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SNP: rs118203576,
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gnomAD: rs118203576,
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ClinVar: RCV000005405, RCV000042078, RCV000118691, RCV000163265, RCV000224245, RCV000303027
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</span>
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<span class="mim-text-font">
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<p>This variant, formerly titled TUBEROUS SCLEROSIS 1, has been reclassified based on the findings of Kwiatkowska et al. (1998). </p><p>In patients with tuberous sclerosis-1 (191100), the only missense mutation among the 32 mutations found by van Slegtenhorst et al. (1997) in the TSC1 gene was an A-to-G transition at nucleotide 1981, leading to a lys585-to-arg (K585R) amino acid change. </p><p>Kwiatkowska et al. (1998) identified the c.1981A-G mutation in the TSC1 gene, which they stated resulted in a K587R substitution, in a patient with sporadic TSC and his unaffected parent, suggesting that the variant is nonpathogenic. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 TUBEROUS SCLEROSIS 1</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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TSC1, 2-BP DEL, 2122AC
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<br />
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SNP: rs118203597,
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ClinVar: RCV000005406, RCV000042102, RCV000713907, RCV003162210, RCV004797756
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Kwiatkowska et al. (1999) described a patient with severe tuberous sclerosis (191100) in whom a mutated TSC1 allele was present in only one-third of leukocytes and in different proportions in other tissues. The case illustrated the importance of considering mosaicism and the limitation of molecular diagnostic methods. The infant girl was born to young healthy parents. Her development was normal until the age of 18 months, when myoclonic seizures occurred. Although the seizures stopped with corticotropin therapy, the child subsequently learned few additional words and withdrew from interaction with her parents and others. At the age of 12 years, she began to have absence seizures. Evaluation revealed a normal body habitus but limited activity and diminished social interaction. Formal testing showed an IQ score of less than 40. Several angiofibromas were present in the malar regions of the face. MRI and CT of the brain showed several calcified subependymal nodules, 2 large cortical tubers (one of which was calcified), and many smaller cortical tubers. Results of renal ultrasonography, echocardiography, and retinal examination were all normal. In exon 15 of the TSC1 gene, a 2-bp deletion, 2122delAC, was found. This deletion changed the TSC1 protein sequence after amino acid residue 634 and truncated it at residue 685; in contrast, the normal TSC1 protein has 1164 residues. DNA from urine and hair roots formed heteroduplexes, indicating that they contained the mutant allele. However, a sample of buccal-mucosa DNA had no heteroduplex product, suggesting that the mutant allele was absent in that sample. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 TUBEROUS SCLEROSIS 1</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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TSC1, 23-BP DUP
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<br />
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SNP: rs118203557,
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ClinVar: RCV000005407, RCV000054946, RCV000713905
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Smith and Sperling (1999) reported the results of mutation analysis in a sporadic case of tuberous sclerosis (191100) first identified in intrauterine life on the basis of the presence of cardiac rhabdomyomas. Postnatally, this infant was also found to have subependymal nodules on brain computed tomographic scan. Hypomelanotic macules were not detected neonatally or at 12 months of age. The specific mutation identified in this patient was duplication of a 23-bp segment of DNA between two 9-bp repeated sequence elements within exon 15 of the TSC1 gene. These repeat elements were located between nucleotides 1892 and 1900 and between nucleotides 1915 and 1923. Smith and Sperling (1999) considered it likely that the presence of these 2 repeated elements predisposed to misalignment of DNA strands and unequal crossing-over. The mechanism of origin of rhabdomyomas in tuberous sclerosis was reviewed. Loss of heterozygosity in the tuberous sclerosis gene regions had been reported in cardiac rhabdomyomas; however, these lesions are self limiting in their growth. The basis for this self-limiting proliferation was not clear. One interesting postulation was that cardiac rhabdomyomas may be due to delay or failure of apoptosis which occurs as part of the normal remodeling process in the heart. </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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<h4>
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<span class="mim-font">
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<strong>.0006 LYMPHANGIOLEIOMYOMATOSIS</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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TSC1, CYS165TER
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<br />
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SNP: rs118203388,
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ClinVar: RCV000005408
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a Japanese patient with isolated pulmonary lymphangioleiomyomatosis (LAM; 606690), Sato et al. (2002) identified a C-to-A transversion at nucleotide 716 in exon 6 of the TSC1 gene, resulting in a cys165-to-ter mutation. Complete inactivation of the TSC1 gene concordant with the Knudson tumor suppressor model (Knudson, 1971) was observed in this patient, who had a TSC1 germline mutation and TSC1 LOH for 2 chromosome 9 markers, D9S149 and D9S1198. Since there was a germline mutation in this case, the isolated pulmonary LAM could be considered monosymptomatic TSC; however, the patient had no clinical features characteristic of TSC. </p>
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</span>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</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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TSC1, HIS732TYR
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<br />
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SNP: rs118203657,
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gnomAD: rs118203657,
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ClinVar: RCV000005409, RCV000005410, RCV000034607, RCV000054851, RCV000118692, RCV000129684, RCV000278906
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>This variant, formerly titled FOCAL CORTICAL DYSPLASIA OF TAYLOR, TYPE IIB and TUBEROUS SCLEROSIS 1, has been reclassified based on the findings of Gumbinger et al. (2009) and Rendtorff et al. (2005). </p><p>Becker et al. (2002) showed that an amino acid change in residue 732 of hamartin from histidine to tyrosine (H732Y) was present in 14 of 40 (35%) cases of focal cortical dysplasia of the Taylor balloon cell type (see 607341) as compared with 2 of 200 (1%) controls. The change was produced by a C-to-T transition at nucleotide 2415 in exon 17 of the TSC1 gene. Exon 17 was the site of a number of other polymorphisms associated with focal cortical dysplasia, as were exons 14 and 22. The H732Y mutation had previously been observed at low frequencies in tuberous sclerosis (191100) and in unaffected individuals (Jones et al., 1997; van Slegtenhorst et al., 1999). Becker et al. (2002) interpreted the change and others as germline polymorphisms that predispose toward the cerebral lesion when combined with LOH in the other allele. The H732T substitution is located in a region of the hamartin protein involved in the interaction domain with tuberin, the product of the TSC2 gene (191092). </p><p>In a detailed genotype-phenotype analysis of 33 patients with focal cortical dysplasia, including 23 with FCD type II, Gumbinger et al. (2009) identified several sequence variations in the TSC1 and TSC2 genes in both lesional brain tissue and blood of the patients, but in similar frequencies to that of the normal population. Most of the sequence alterations were silent. Gumbinger et al. (2009) concluded that focal cortical dysplasia is not caused by mutation in the TSC genes and does not appear to be promoted by TSC polymorphisms. Rendtorff et al. (2005) considered the H732Y mutation, which had been identified by Jones et al. (1997) in individuals without tuberous sclerosis, to be a polymorphism. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0008 TUBEROUS SCLEROSIS 1</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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TSC1, MET224ARG
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<br />
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SNP: rs118203426,
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ClinVar: RCV000005411, RCV000042336
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 4 affected individuals from a family with tuberous sclerosis (191100), Nellist et al. (2009) identified a heterozygous 671T-G transversion in the TSC1 gene, resulting in a met224-to-arg (M224R) substitution. The proband had definite TSC with multiple shagreen patches, hypomelanotic macules, ungual fibromas, dental pits, epilepsy and severe mental disability. One parent and both siblings also fulfilled the diagnostic criteria for definite TSC, including seizures, cortical tubers, and below-average intelligence. All affected individuals also carried a neutral 3103G-A polymorphism (gly1035 to ser; G1035S) in cis with the M224R mutation. In vitro functional expression studies showed that M224R-mutant protein did not decrease phosphorylation of p70-S6K (608938), indicating constitutive activation of the MTOR (FRAP1; 601231)-S6K pathway, whereas the G1035S variant and wildtype protein reduced S6K phosphorylation. These findings indicated that M224R mutation was responsible for the phenotype in this family. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0009 TUBEROUS SCLEROSIS 1</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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TSC1, LEU180PRO
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<br />
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SNP: rs118203396,
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ClinVar: RCV000005412, RCV000042306
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 5 affected individuals from a 3-generation family with tuberous sclerosis (191100), Nellist et al. (2009) identified a heterozygous 539T-C transition in the TSC1 gene, resulting in a leu180-to-pro (L180P) substitution. In vitro functional expression studies detected the mutant protein at low levels and showed that the mutant protein did not inhibit S6K (608938) phosphorylation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0010 FOCAL CORTICAL DYSPLASIA, TYPE II, SOMATIC</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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TSC1, ARG22TRP
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<br />
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SNP: rs749030456,
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gnomAD: rs749030456,
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ClinVar: RCV000477710, RCV000573120, RCV000695216, RCV001526808, RCV001721544
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In brain tissue resected from 3 unrelated children (FCD81, FCD98, FCD123) with seizures due to focal cortical dysplasia type II (FCORD2; 607341), Lim et al. (2017) identified a de novo somatic c.64C-T transition (c.64C-T, NM_000368.4) in the TSC1 gene, resulting in an arg22-to-trp (R22W) substitution at a highly conserved residue. The mutation, which was found by targeted sequencing of genes in the MTOR pathway, was not found in the 1000 Genomes Project database, but was present at a very low frequency (1.65 x 10(-5)) in the ExAC database. The mutant allele frequency in brain tissue was very low, about 1 to 2.8%. Patient dystrophic brain cells and R22W-transfected cells showed increased S6K phosphorylation (RPS6KB1; 608938) compared to wildtype, consistent with hyperactivation of the mTOR pathway. Mutant TSC1 also showed impaired binding to TSC2, indicating disruption of the TSC1-TSC2 complex. Abnormal S6K phosphorylation in transfected cells was inhibited by treatment with rapamycin. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0011 FOCAL CORTICAL DYSPLASIA, TYPE II, SOMATIC</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TSC1, ARG204CYS
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<br />
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SNP: rs1060505021,
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ClinVar: RCV000477742, RCV000694777
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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 brain tissue resected from a 6-year-old girl (FCD64) with seizures due to focal cortical dysplasia type II (FCORD2; 607341), Lim et al. (2017) identified a de novo somatic c.610C-T transition (c.610C-T, NM_000368.4) in the TSC1 gene, resulting in an arg204-to-cys (R204C) substitution at a highly conserved residue. The mutation, which was found by targeted sequencing of genes in the MTOR pathway, was not found in the 1000 Genomes Project or ExAC databases. The mutant allele frequency in brain tissue was very low, less than 2%. Patient dystrophic brain cells and R204C-transfected cells showed increased S6K phosphorylation (RPS6KB1; 608938) compared to wildtype, consistent with hyperactivation of the mTOR pathway. Mutant TSC1 also showed impaired binding to TSC2, indicating disruption of the TSC1-TSC2 complex. Abnormal S6K phosphorylation in transfected cells was inhibited by treatment with rapamycin. </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>REFERENCES</strong>
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|
</span>
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</h4>
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<div>
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<p />
|
|
</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
|
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Abs, E., Goorden, S. M. I., Schreiber, J., Overwater, I. E., Hoogeveen-Westerveld, M., Bruinsma, C. F., Aganovic, E., Borgesius, N. Z., Nellist, M., Elgersma, Y.
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|
<strong>TORC1-dependent epilepsy caused by acute biallelic Tsc1 deletion in adult mice.</strong>
|
|
Ann. Neurol. 74: 569-579, 2013.
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[PubMed: 23720219]
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[Full Text: https://doi.org/10.1002/ana.23943]
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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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Adhikari, D., Zheng, W., Shen, Y., Gorre, N., Hamalainen, T., Cooney, A. J., Huhtaniemi, I., Lan, Z.-J., Liu, K.
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<strong>Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles.</strong>
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Hum. Molec. Genet. 19: 397-410, 2010.
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[PubMed: 19843540]
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[Full Text: https://doi.org/10.1093/hmg/ddp483]
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<p class="mim-text-font">
|
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Ali, J. B. M., Sepp, T., Ward, S., Green, A. J., Yates, J. R. W.
|
|
<strong>Mutations in the TSC1 gene account for a minority of patients with tuberous sclerosis.</strong>
|
|
J. Med. Genet. 35: 969-972, 1998.
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[PubMed: 9863590]
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[Full Text: https://doi.org/10.1136/jmg.35.12.969]
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</p>
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<li>
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<p class="mim-text-font">
|
|
Astrinidis, A., Senapedis, W., Henske, E. P.
|
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<strong>Hamartin, the tuberous sclerosis complex 1 gene product, interacts with polo-like kinase 1 in a phosphorylation-dependent manner.</strong>
|
|
Hum. Molec. Genet. 15: 287-297, 2006.
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[PubMed: 16339216]
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[Full Text: https://doi.org/10.1093/hmg/ddi444]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Au, K. S., Williams, A. T., Roach, E. S., Batchelor, L., Sparagana, S. P., Delgado, M. R., Wheless, J. W., Baumgartner, J. E., Roa, B. B., Wilson, C. M., Smith-Knuppel, T. K., Cheung, M.-Y. C., Whittemore, V. H., King, T. M., Northrup, H.
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|
<strong>Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States.</strong>
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Genet. Med. 9: 88-100, 2007.
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[PubMed: 17304050]
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[Full Text: https://doi.org/10.1097/gim.0b013e31803068c7]
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</p>
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<li>
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<p class="mim-text-font">
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Becker, A. J., Urbach, H., Scheffler, B., Baden, T., Normann, S., Lahl, R., Pannek, H. W., Tuxhorn, I., Elger, C. E., Schramm, J., Wiestler, O. D., Blumcke, I.
|
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<strong>Focal cortical dysplasia of Taylor's balloon cell type: mutational analysis of the TSC1 gene indicates a pathogenic relationship to tuberous sclerosis.</strong>
|
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Ann. Neurol. 52: 29-37, 2002.
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[PubMed: 12112044]
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[Full Text: https://doi.org/10.1002/ana.10251]
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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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Benit, P., Kara-Mostefa, A., Hadj-Rabia, S., Munnich, A., Bonnefont, J.-P.
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<strong>Protein truncation test for screening hamartin gene mutations and report of new disease-causing mutations.</strong>
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|
Hum. Mutat. 14: 428-432, 1999.
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[PubMed: 10533069]
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[Full Text: https://doi.org/10.1002/(SICI)1098-1004(199911)14:5<428::AID-HUMU9>3.0.CO;2-5]
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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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Benvenuto, G., Li, S., Brown, S. J., Braverman, R., Vass, W. C., Cheadle, J. P., Halley, D. J. J., Sampson, J. R., Wienecke, R., DeClue, J. E.
|
|
<strong>The tuberous sclerosis-1 (TSC1) gene product hamartin suppresses cell growth and augments the expression of the TSC2 product tuberin by inhibiting its ubiquitination.</strong>
|
|
Oncogene 19: 6306-6316, 2000.
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[PubMed: 11175345]
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[Full Text: https://doi.org/10.1038/sj.onc.1204009]
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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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|
Bjornsson, J., Short, M. P., Kwiatkowski, D. J., Henske, E. P.
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<strong>Tuberous sclerosis-associated renal cell carcinoma.</strong>
|
|
Am. J. Path. 149: 1201-1208, 1996.
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[PubMed: 8863669]
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</li>
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<li>
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<p class="mim-text-font">
|
|
Bonnet, C. S., Aldred, M., von Ruhland, C., Harris, R., Sandford, R., Cheadle, J. P.
|
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<strong>Defects in cell polarity underlie TSC and ADPKD-associated cystogenesis.</strong>
|
|
Hum. Molec. Genet. 18: 2166-2176, 2009.
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|
[PubMed: 19321600]
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[Full Text: https://doi.org/10.1093/hmg/ddp149]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Carbonara, C., Longa, L., Grosso, E., Borrone, C., Garre, M. G., Brisigotti, M., Migone, N.
|
|
<strong>9q34 loss of heterozygosity in a tuberous sclerosis astrocytoma suggests a growth suppressor-like activity also for the TSC1 gene.</strong>
|
|
Hum. Molec. Genet. 3: 1829-1832, 1994.
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|
[PubMed: 7849708]
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[Full Text: https://doi.org/10.1093/hmg/3.10.1829]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Carbonara, C., Longa, L., Grosso, E., Mazzucco, G., Borrone, C., Garre, M. L., Brisigotti, M., Filippi, G., Scabar, A., Giannotti, A., Falzoni, P., Monga, G., Garini, G., Gabrielli, M., Riegler, P., Danesino, C., Ruggieri, M., Magro, G., Migone, N.
|
|
<strong>Apparent preferential loss of heterozygosity at TSC2 over TSC1 chromosomal region in tuberous sclerosis hamartomas.</strong>
|
|
Genes Chromosomes Cancer 15: 18-25, 1996.
|
|
|
|
|
|
[PubMed: 8824721]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/(SICI)1098-2264(199601)15:1<18::AID-GCC3>3.0.CO;2-7]
|
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Cheadle, J. P., Dobbie, L., Idziaszczyk, S., Hodges, A. K., Smith, A. J. H., Sampson, J. R., Young, J.
|
|
<strong>Genomic organization and comparative analysis of the mouse tuberous sclerosis 1 (Tsc1) locus.</strong>
|
|
Mammalian Genome 11: 1135-1138, 2000.
|
|
|
|
|
|
[PubMed: 11130985]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s003350010203]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Cheadle, J. P., Reeve, M. P., Sampson, J. R., Kwiatkowski, D. J.
|
|
<strong>Molecular genetic advances in tuberous sclerosis.</strong>
|
|
Hum. Genet. 107: 97-114, 2000.
|
|
|
|
|
|
[PubMed: 11030407]
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|
|
[Full Text: https://doi.org/10.1007/s004390000348]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Choi, Y.-J., Di Nardo, A., Kramvis, I., Meikle, L., Kwiatkowski, D. J., Sahin, M., He, X.
|
|
<strong>Tuberous sclerosis complex proteins control axon formation.</strong>
|
|
Genes Dev. 22: 2485-2495, 2008.
|
|
|
|
|
|
[PubMed: 18794346]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1101/gad.1685008]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Dabora, S. L., Jozwiak, S., Franz, D. N., Roberts, P. S., Nieto, A., Chung, J., Choy, Y.-S., Reeve, M. P., Thiele, E., Egelhoff, J. C., Kasprzyk-Obara, J., Domanska-Pakiela, D., Kwiatkowski, D. J.
|
|
<strong>Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs.</strong>
|
|
Am. J. Hum. Genet. 68: 64-80, 2001.
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|
|
[PubMed: 11112665]
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|
|
[Full Text: https://doi.org/10.1086/316951]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
DiBella, L. M., Park, A., Sun, Z.
|
|
<strong>Zebrafish Tsc1 reveals functional interactions between the cilium and the TOR pathway.</strong>
|
|
Hum. Molec. Genet. 18: 595-606, 2009.
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|
|
[PubMed: 19008302]
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[Full Text: https://doi.org/10.1093/hmg/ddn384]
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</p>
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</li>
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