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Entry
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- *614041 - RB TRANSCRIPTIONAL COREPRESSOR 1; RB1
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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">*614041</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#evolution">Evolution</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation">
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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/614041">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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</nav>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000139687;t=ENST00000267163" 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=5925" 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=614041" 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=ENSG00000139687;t=ENST00000267163" 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_000321,NM_001407165,NM_001407166,NM_001407167,NM_001407168" 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_000321" 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=614041" 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://www.proteinatlas.org/search/RB1" 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/35895,132164,190946,190959,190963,190968,292421,521212,793945,793949,793951,793953,793955,793957,793959,793961,793963,793965,793967,793971,793976,793979,793981,793983,793987,793988,793990,793992,793995,793999,794001,794003,794005,794007,794009,794011,794015,794016,801730,804752,804754,804756,804758,804760,1088287,1088289,1088291,1088293,1088295,1088297,1088299,1088301,1088303,1088305,1088307,1088309,1088311,1088313,1088315,1088317,1088319,1088321,1088323,1088325,1088327,1088329,1088331,1088333,1088335,1088337,2865464,24660140,24754020,26252120,29123599,30961711,32394690,49659965,50429249,50429251,50429253,56182557,62087156,83778582,108773787,119629198,119629199,158255952,194387624,194390566,1473096547,1473096549,1473096551,1473096553,1473096555,1473096557,1473096559,1473096561,1473096563,1473096565,1473096567,1473096569,1473096571,1473096573,1473096575,1473096577,1473096579,1473096581,1473096583,1473096585,1473096587,1473096589,1473096591,1473096593,1473096595,1933113285,1933113287,1933113289,1933113291,1933113293,1933113295,1933113297,1933113299,1933113301,1933113303,2245367901,2245367912,2245368001,2245368022" 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/P06400" 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=5925" 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=ENSG00000139687;t=ENST00000267163" 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=RB1" 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=RB1" 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+5925" 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/RB1" 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:5925" 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/5925" 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=chr13&hgg_gene=ENST00000267163.6&hgg_start=48303751&hgg_end=48481890&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:9884" 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:9884" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/rb1" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=614041[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=614041[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/RB1/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/ENSG00000139687" 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=RB1" 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=RB1" 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=RB1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=RB1&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/PA295" 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:9884" 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/FBgn0038390.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:97874" 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/RB1#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:97874" 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/5925/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=5925" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00003020;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-040428-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:5925" 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=RB1&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> 19906005, 370967009<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>
|
|
614041
|
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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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RB TRANSCRIPTIONAL COREPRESSOR 1; RB1
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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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p105-Rb
|
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</span>
|
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</h4>
|
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</div>
|
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</div>
|
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=RB1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">RB1</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>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/13/162?start=-3&limit=10&highlight=162">13q14.2</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr13:48303751-48481890&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'})">13:48,303,751-48,481,890</a> </span>
|
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</em>
|
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</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>
|
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<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>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=109800,259500,180200,180200,182280" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="5">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/13/162?start=-3&limit=10&highlight=162">
|
|
13q14.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Bladder cancer, somatic
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/109800"> 109800 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<p><a href="#16" class="mim-tip-reference" title="Dryja, T., Cavenee, W., Epstein, J., Rapaport, J., Goorin, A., Koufos, A. <strong>Chromosome 13 homozygosity in osteogenic sarcoma without retinoblastoma. (Abstract)</strong> Am. J. Hum. Genet. 36: 28S, 1984."None>Dryja et al. (1984)</a> cloned DNA fragments from chromosome 13. Three of these identified RFLPs from region 13q12-q22, which contains the retinoblastoma (<a href="/entry/180200">180200</a>) 'locus.'</p><p><a href="#21" class="mim-tip-reference" title="Friend, S. H., Bernards, R., Rogelj, S., Weinberg, R. A., Rapaport, J. M., Albert, D. M., Dryja, T. P. <strong>A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma.</strong> Nature 323: 643-646, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2877398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2877398</a>] [<a href="https://doi.org/10.1038/323643a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2877398">Friend et al. (1986)</a> isolated a cDNA that detects a chromosomal segment having the properties of the gene at the retinoblastoma locus. The gene was found to be expressed in many tumor types, but no RNA transcript was found in retinoblastomas or osteosarcomas. The locus spanned at least 70 kb of DNA. <a href="#21" class="mim-tip-reference" title="Friend, S. H., Bernards, R., Rogelj, S., Weinberg, R. A., Rapaport, J. M., Albert, D. M., Dryja, T. P. <strong>A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma.</strong> Nature 323: 643-646, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2877398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2877398</a>] [<a href="https://doi.org/10.1038/323643a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2877398">Friend et al. (1986)</a> started with a 1.5 kb DNA sequence which could detect deletions involving 13q14 in 3 of 37 retinoblastomas. They then used chromosome walking techniques to isolate and map 30 kb of surrounding genomic DNA. One of the single-copy fragments recognized a DNA sequence in the mouse genome and also in human chromosome 13. The conservation of this DNA sequence between mouse and humans suggested that the cloned fragment contained a coding exon of a gene. Therefore, they tested the ability of this fragment to hybridize to RNA derived from retinoblastoma cells and from human retinal cells. They found that indeed it recognized a 4.7-kb RNA transcript in the retinal cell line but that this transcript was not detectable in 4 retinoblastomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2877398" 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>As outlined by <a href="#6" class="mim-tip-reference" title="Cavenee, W. K. <strong>The genetic basis of neoplasia: the retinoblastoma paradigm.</strong> Trends Genet. 2: 299-300, 1986."None>Cavenee (1986)</a>, when the cDNA described by <a href="#21" class="mim-tip-reference" title="Friend, S. H., Bernards, R., Rogelj, S., Weinberg, R. A., Rapaport, J. M., Albert, D. M., Dryja, T. P. <strong>A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma.</strong> Nature 323: 643-646, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2877398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2877398</a>] [<a href="https://doi.org/10.1038/323643a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2877398">Friend et al. (1986)</a> was used as a probe to screen RNA samples from different tumor types, it was shown to hybridize to all of those tested except retinoblastomas and retinoblastoma-associated osteosarcomas. Furthermore, use of this cDNA to analyze the genomic structure of its homologous locus in 50 retinoblastomas or associated osteosarcomas showed that about 30% had somatically altered genomic loci. These alterations took the form of fragments of altered mobility (suggesting gene rearrangements), underrepresented fragments (suggesting heterozygous deletions), and missing fragments (suggesting homozygous deletions). Since one of the homozygous deletions was entirely contained within the genomic locus homologous to the cDNA probe, it was suggested that this expressed gene was indeed the RB1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2877398" 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="Dryja, T. P., Friend, S., Weinberg, R. A. <strong>Isolation of a cDNA fragment derived from human retina mRNA which detects a locus within 13q14 often deleted in retinoblastomas. (Abstract)</strong> Am. J. Hum. Genet. 39: A29, 1986."None>Dryja et al. (1986)</a> isolated a cDNA fragment derived from human retinal mRNA that detected a locus within 13q14 that is often deleted in retinoblastoma.</p><p><a href="#42" class="mim-tip-reference" title="Lee, W.-H., Shew, J.-Y., Hong, F. D., Sery, T. W., Donoso, L. A., Young, L.-J., Bookstein, R., Lee, E. Y.-H. P. <strong>The retinoblastoma susceptibility gene encodes a nuclear phosphoprotein associated with DNA binding activity.</strong> Nature 329: 642-645, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3657987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3657987</a>] [<a href="https://doi.org/10.1038/329642a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3657987">Lee et al. (1987)</a> prepared a rabbit antiserum against the RB protein studied by <a href="#33" class="mim-tip-reference" title="Horsthemke, B., Greger, V., Barnert, H. J., Hopping, W., Passarge, E. <strong>Detection of submicroscopic deletions and a DNA polymorphism at the retinoblastoma locus.</strong> Hum. Genet. 76: 257-261, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2885256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2885256</a>] [<a href="https://doi.org/10.1007/BF00283619" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2885256">Horsthemke et al. (1987)</a> and showed that it was present in all cell lines expressing normal RB mRNA but was not detected in 5 retinoblastoma cell lines. The RB protein can be metabolically labeled with (32)P-phosphoric acid, indicating that it is a phosphoprotein. Biochemical fractionation and immunofluorescence studies demonstrated that most of the protein is located in the nucleus. Furthermore, the protein was retained by and could be eluted from DNA-cellulose columns, suggesting a DNA binding activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3657987+2885256" 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 gene encoding a messenger RNA of 4.6 kb, located in the proximity of esterase D (<a href="/entry/133280">133280</a>), was identified by <a href="#41" class="mim-tip-reference" title="Lee, W.-H., Bookstein, R., Hong, F., Young, L.-J., Shew, J.-Y., Lee, E. Y.-H. P. <strong>Human retinoblastoma susceptibility gene: cloning, identification, and sequence.</strong> Science 235: 1394-1399, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3823889/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3823889</a>] [<a href="https://doi.org/10.1126/science.3823889" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3823889">Lee et al. (1987)</a> as the retinoblastoma susceptibility gene on the basis of chromosomal location, homozygous deletion, and tumor-specific alterations in expression. Transcription of the gene was abnormal in all of 6 retinoblastomas examined: in 2, mRNA was not detectable, whereas 4 others expressed variable quantities of the mRNA with decreased molecular size of about 4.0 kb. In contrast, full-length RB mRNA was present in human fetal retina and placenta, and in other tumors such as neuroblastoma and medulloblastoma. The sequence of cDNA clones indicated a hypothetical protein of 816 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3823889" 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="#77" class="mim-tip-reference" title="Whyte, P., Buchkovich, K. J., Horowitz, J. M., Friend, S. H., Raybuck, M., Weinberg, R. A., Harlow, E. <strong>Association between an oncogene and an anti-oncogene: the adenovirus E1A proteins bind to the retinoblastoma gene product.</strong> Nature 334: 124-129, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2968522/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2968522</a>] [<a href="https://doi.org/10.1038/334124a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2968522">Whyte et al. (1988)</a> demonstrated that a 105,000-Da cellular protein, which is one of the cellular targets implicated in the process of transformation by the adenovirus E1A proteins, is in fact the product of the RB1 gene. This interaction with the formation of a stable protein/protein complex was the first demonstration of a physical link between an oncogene and an antioncogene. A similar case can be made for numerous other disorders, many of which are more common. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2968522" 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="#69" class="mim-tip-reference" title="Toguchida, J., McGee, T. L., Paterson, J. C., Eagle, J. R., Tucker, S., Yandell, D. W., Dryja, T. P. <strong>Complete genomic sequence of the human retinoblastoma susceptibility gene.</strong> Genomics 17: 535-543, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7902321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7902321</a>] [<a href="https://doi.org/10.1006/geno.1993.1368" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7902321">Toguchida et al. (1993)</a> reported the complete genomic sequence of the RB1 gene, which was contained in a 180,388-bp contig. The gene produces a 4.7-kb transcript that encodes a nuclear phosphoprotein consisting of 928 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7902321" 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="#30" class="mim-tip-reference" title="Hong, F. D., Huang, H.-J. S., To, H., Young, L.-J. S., Oro, A., Bookstein, R., Lee, E. Y.-H. P., Lee, W.-H. <strong>Structure of the human retinoblastoma gene.</strong> Proc. Nat. Acad. Sci. 86: 5502-5506, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2748600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2748600</a>] [<a href="https://doi.org/10.1073/pnas.86.14.5502" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2748600">Hong et al. (1989)</a> demonstrated that the RB transcript is encoded in 27 exons dispersed over about 200 kb of genomic DNA. The length of individual exons ranges from 31 to 1,889 bp. The largest intron spans more than 60 kb and the smallest one has only 80 bp. Deletion of exons 13-17 is frequently observed in various types of tumors, including retinoblastoma, breast cancer, and osteosarcoma, and the presence of a potential 'hotspot' for recombination in the region was predicted. A putative 'leucine-zipper' motif is exclusively encoded by exon 20. Transcription of RB is initiated at multiple positions and the sequences surrounding the initiation sites have a high G+C content. Several features of the RB promoter are reminiscent of those associated with many so-called housekeeping genes, consistent with the ubiquitous expression of the RB gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2748600" 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="#67" class="mim-tip-reference" title="Stone, J. C., Crosby, J. L., Kozak, C. A., Schievella, A. R., Bernards, R., Nadeau, J. H. <strong>The murine retinoblastoma homolog maps to chromosome 14 near Es-10.</strong> Genomics 5: 70-75, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2570031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2570031</a>] [<a href="https://doi.org/10.1016/0888-7543(89)90088-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2570031">Stone et al. (1989)</a> mapped the mouse homolog of the human retinoblastoma gene, symbolized Rb1, to chromosome 14 by analysis of somatic cell hybrids. In recombinant inbred strains, the findings suggested close linkage of Rb1 and Es10, which appears to be the mouse homolog of ESD (<a href="/entry/133280">133280</a>). By in situ hybridization, <a href="#55" class="mim-tip-reference" title="Ono, T., Yoshida, M. C. <strong>Chromosomal assignment of retinoblastoma 1 gene (RB1) to mouse 14D3 and rat 15q12 by fluorescence in situ hybridization.</strong> Jpn. J. Genet. 68: 617-621, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8031579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8031579</a>] [<a href="https://doi.org/10.1266/jjg.68.617" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8031579">Ono and Yoshida (1993)</a> assigned the RB1 gene to mouse 14D3 and the rat homolog to 15q12. A unique sequence human RB1 cosmid DNA probe was used by <a href="#71" class="mim-tip-reference" title="Verma, R. S., Ramesh, K. H., Samonte, R. V., Conte, R. A. <strong>Mapping the homolog of the human Rb1 gene to chromosome 14 of higher primates.</strong> Mammalian Genome 7: 591-592, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8678979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8678979</a>] [<a href="https://doi.org/10.1007/s003359900175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8678979">Verma et al. (1996)</a> to localize the RB1 homolog in chimpanzee, gorilla, and orangutan to chromosome 14 by fluorescence in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8031579+8678979+2570031" 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>Analysis of the RB1 gene sequence by <a href="#69" class="mim-tip-reference" title="Toguchida, J., McGee, T. L., Paterson, J. C., Eagle, J. R., Tucker, S., Yandell, D. W., Dryja, T. P. <strong>Complete genomic sequence of the human retinoblastoma susceptibility gene.</strong> Genomics 17: 535-543, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7902321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7902321</a>] [<a href="https://doi.org/10.1006/geno.1993.1368" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7902321">Toguchida et al. (1993)</a> indicated a high ratio of (A+T)/(G+C) and a high density of Line-1 (L1) repeat sequences, suggesting that the gene maps to G-bands 13q14.12 or 13q14.2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7902321" 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="#14" class="mim-tip-reference" title="DeCaprio, J. A., Ludlow, J. W., Lynch, D., Furukawa, Y., Griffin, J., Piwnica-Worms, H., Huang, C.-M., Livingston, D. M. <strong>The product of the retinoblastoma susceptibility gene has properties of a cell cycle regulatory element.</strong> Cell 58: 1085-1095, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2673542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2673542</a>] [<a href="https://doi.org/10.1016/0092-8674(89)90507-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2673542">DeCaprio et al. (1989)</a>, <a href="#3" class="mim-tip-reference" title="Buchkovich, K., Duffy, L. A., Harlow, E. <strong>The retinoblastoma protein is phosphorylated during specific phases of the cell cycle.</strong> Cell 58: 1097-1105, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2673543/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2673543</a>] [<a href="https://doi.org/10.1016/0092-8674(89)90508-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2673543">Buchkovich et al. (1989)</a>, and <a href="#8" class="mim-tip-reference" title="Chen, P.-L., Scully, P., Shew, J.-Y., Wang, J. Y. J., Lee, W.-H. <strong>Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentiation.</strong> Cell 58: 1193-1198, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2673546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2673546</a>] [<a href="https://doi.org/10.1016/0092-8674(89)90517-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2673546">Chen et al. (1989)</a> demonstrated that the RB1 gene product has the properties of a cell cycle regulatory element and that its function is modulated by a phosphorylation/dephosphorylation mechanism during cell proliferation and differentiation. In G0/G1 cells, virtually all the RB protein is unphosphorylated, whereas during S and G2 phases, it is largely, if not exclusively, phosphorylated. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2673546+2673542+2673543" 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="Shiio, Y., Yamamoto, T., Yamaguchi, N. <strong>Negative regulation of Rb expression by the p53 gene product.</strong> Proc. Nat. Acad. Sci. 89: 5206-5210, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1608930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1608930</a>] [<a href="https://doi.org/10.1073/pnas.89.12.5206" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1608930">Shiio et al. (1992)</a> found evidence that wildtype p53 suppresses transcription of the RB gene. From deletion and mutagenesis experiments, a cis-acting element (GGAAGTGA) susceptible to regulation by p53 was mapped within the RB promoter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1608930" 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="Mancini, M. A., Shan, B., Nickerson, J. A., Penman, S., Lee, W.-H. <strong>The retinoblastoma gene product is a cell cycle-dependent, nuclear matrix-associated protein.</strong> Proc. Nat. Acad. Sci. 91: 418-422, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8278403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8278403</a>] [<a href="https://doi.org/10.1073/pnas.91.1.418" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8278403">Mancini et al. (1994)</a> demonstrated by immunoblotting and immunolabeling that a significant portion of hypophosphorylated Rb associates with the nuclear matrix during the early G1 phase. They suggested that Rb interactions with a nuclear matrix may be important for its ability to regulate cell cycle progression. Mutant Rb in tumor cells did not associate with the matrix, whereas Rb-reconstituted cells contained abundant matrix-bound Rb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8278403" 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="#76" class="mim-tip-reference" title="Weinberg, R. A. <strong>The retinoblastoma protein and cell cycle control.</strong> Cell 81: 323-330, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7736585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7736585</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90385-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7736585">Weinberg (1995)</a> reviewed the role of the RB protein in the control of the cell cycle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7736585" 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="Fearon, E. R. <strong>Human cancer syndromes: clues to the origin and nature of cancer.</strong> Science 278: 1043-1050, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9353177/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9353177</a>] [<a href="https://doi.org/10.1126/science.278.5340.1043" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9353177">Fearon (1997)</a> provided a schematic representation of the cellular localization and presumed functions of the proteins encoded by inherited cancer genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9353177" 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="#48" class="mim-tip-reference" title="Luo, R. X., Postigo, A. A., Dean, D. C. <strong>Rb interacts with histone deacetylase to repress transcription.</strong> Cell 92: 463-473, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9491888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9491888</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80940-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9491888">Luo et al. (1998)</a> demonstrated that Rb can repress transcription of endogenous cell cycle genes containing E2F sites through recruitment of histone deacetylase, which deacetylates histones on the promoter, thereby promoting formation of nucleosomes that inhibit transcription. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9491888" 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>RB inhibits progression from G1 to S phase of the cell cycle and associates with a number of cellular proteins. <a href="#83" class="mim-tip-reference" title="Zhang, H. S., Postigo, A. A., Dean, D. C. <strong>Active transcriptional repression by the Rb-E2F complex mediates G1 arrest triggered by p16(INK4a), TGF-beta, and contact inhibition.</strong> Cell 97: 53-61, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10199402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10199402</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80714-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10199402">Zhang et al. (1999)</a> presented evidence that RB must normally interact with the E2F family of transcription factors to arrest cells in G1, and that this arrest results from active transcriptional repression by the RB-E2F complex, not from inactivation of E2F. Thus, a major role of E2F in cell cycle regulation is assembly of this repressor complex. <a href="#83" class="mim-tip-reference" title="Zhang, H. S., Postigo, A. A., Dean, D. C. <strong>Active transcriptional repression by the Rb-E2F complex mediates G1 arrest triggered by p16(INK4a), TGF-beta, and contact inhibition.</strong> Cell 97: 53-61, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10199402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10199402</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80714-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10199402">Zhang et al. (1999)</a> demonstrated that active repression by the RB-E2F complex mediates the G1 arrest triggered by transforming growth factor-beta (TGFB; <a href="/entry/190180">190180</a>), p16(INK4A) (CDKN2A; <a href="/entry/600160">600160</a>), and contact inhibition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10199402" 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="Harbour, J. W., Luo, R. X., Dei Santi, A., Postigo, A. A., Dean, D. C. <strong>Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1.</strong> Cell 98: 859-869, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10499802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10499802</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81519-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10499802">Harbour et al. (1999)</a> presented evidence that phosphorylation of the C-terminal region of RB by CDK4 (<a href="/entry/123829">123829</a>)/CDK6 (<a href="/entry/603368">603368</a>) initiates successive intramolecular interactions between the C-terminal region and the central pocket. The initial interaction displaces histone deacetylase from the pocket, blocking active transcriptional repression by RB. This facilitates a second interaction that leads to phosphorylation of the pocket by CDK2 (<a href="/entry/116953">116953</a>) and disruption of pocket structure. These intramolecular interactions provide a molecular basis for sequential phosphorylation of RB by CDK4/CDK6 and CDK2. CDK4/CDK6 is activated early in G1, blocking active repression by RB. However, it is not until near the end of G1, when cyclin E (see <a href="/entry/123837">123837</a>) is expressed and CDK2 is activated, that RB is prevented from binding and inactivating E2F. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10499802" 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="Hsieh, J.-K., Chan, F. S. G., O'Connor, D. J., Mittnacht, S., Zhong, S., Lu, X. <strong>RB regulates the stability and the apoptotic function of p53 via MDM2.</strong> Molec. Cell 3: 181-193, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10078201/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10078201</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80309-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10078201">Hsieh et al. (1999)</a> showed that the binding of RB to MDM2 (<a href="/entry/164785">164785</a>) is essential for RB to overcome both the antiapoptotic function of MDM2 and the MDM2-dependent degradation of p53. Since RB specifically rescues the apoptotic function but not the transcriptional activity of p53 from negative regulation by MDM2, transactivation by wildtype p53 is not required for the apoptotic function of p53. These data demonstrated a role of RB in regulating the apoptotic function of p53. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10078201" 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="Hanahan, D., Weinberg, R. A. <strong>The hallmarks of cancer.</strong> Cell 100: 57-70, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10647931/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10647931</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81683-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10647931">Hanahan and Weinberg (2000)</a> referred to deregulation of the retinoblastoma protein pathway as a 'hallmark of cancer.' In the absence of other genetic alterations, deregulation results in lack of differentiation, hyperproliferation, and apoptosis. The RB protein acts as a transcriptional repressor by targeting the E2F transcription factors (e.g., <a href="/entry/189971">189971</a>), whose functions are required for entry into S phase. Increased E2F activity can induce S phase in quiescent cells; this is a central element of most models for the development of cancer. <a href="#47" class="mim-tip-reference" title="Lomazzi, M., Moroni, M. C., Jensen, M. R., Frittoli, E., Helin, K. <strong>Suppression of the p53- or pRB-mediated G1 checkpoint is required for E2F-induced S-phase entry.</strong> Nature Genet. 31: 190-194, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11992123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11992123</a>] [<a href="https://doi.org/10.1038/ng891" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11992123">Lomazzi et al. (2002)</a> showed that increased E2F1 activity can result in S phase entry in diploid fibroblasts only when the p53 (<a href="/entry/191170">191170</a>)-mediated G1 checkpoint is suppressed. They showed that E2F1 can induce S phase in primary mouse fibroblasts lacking Rb protein. These results indicated that in addition to acting as an E2F-dependent transcriptional repressor, RB protein is also required for the cells to retain the G1 checkpoint in response to unprogrammed proliferative signals. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10647931+11992123" 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="Pennaneach, V., Salles-Passador, I., Munshi, A., Brickner, H., Regazzoni, K., Dick, F., Dyson, N., Chen, T.-T., Wang, J. Y. J., Fotedar, R., Fotedar, A. <strong>The large subunit of replication factor C promotes cell survival after DNA damage in an LxCxE motif- and Rb-dependent manner.</strong> Molec. Cell 7: 715-727, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11336696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11336696</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00217-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11336696">Pennaneach et al. (2001)</a> showed that the LxCxE-binding site in RB1 mediates both cell survival and cell cycle arrest after DNA damage. Replication factor C (RFC) complex plays an important role in DNA replication. <a href="#57" class="mim-tip-reference" title="Pennaneach, V., Salles-Passador, I., Munshi, A., Brickner, H., Regazzoni, K., Dick, F., Dyson, N., Chen, T.-T., Wang, J. Y. J., Fotedar, R., Fotedar, A. <strong>The large subunit of replication factor C promotes cell survival after DNA damage in an LxCxE motif- and Rb-dependent manner.</strong> Molec. Cell 7: 715-727, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11336696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11336696</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00217-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11336696">Pennaneach et al. (2001)</a> described a function of the large subunit of RFC, RFC1 (<a href="/entry/102579">102579</a>), in promoting cell survival after DNA damage. RFC1 contains an LxCxE motif, and mutation of this motif abolished the protective effect of RFC1. The inability of wildtype RFC1 to promote cell survival in RB1-null cells was rescued by RB1 but not by RB1 mutants defective in binding LxCxE proteins. RFC thus enhances cell survival after DNA damage in an RB1-dependent manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11336696" 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="#52" class="mim-tip-reference" title="Nielsen, S. J., Schneider, R., Bauer, U.-M., Bannister, A. J., Morrison, A., O'Carroll, D., Firestein, R., Cleary, M., Jenuwein, T., Herrera, R. E., Kouzarides, T. <strong>Rb targets histone H3 methylation and HP1 to promoters.</strong> Nature 412: 561-565, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11484059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11484059</a>] [<a href="https://doi.org/10.1038/35087620" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11484059">Nielsen et al. (2001)</a> demonstrated that SUV39H1 (<a href="/entry/300254">300254</a>) and HP1 (<a href="/entry/604478">604478</a>) are both involved in the repressive functions of the retinoblastoma protein. Rb associates with SUV39H1 and HP1 in vivo by means of its pocket domain. SUV39H1 cooperates with Rb to repress the cyclin E (<a href="/entry/123837">123837</a>) promoter, and in fibroblasts that are disrupted for SUV39H1, the activity of the cyclin E and cyclin A2 (<a href="/entry/123835">123835</a>) genes are specifically elevated. Chromatin immunoprecipitation showed that Rb is necessary to direct methylation of histone H3, and is necessary for binding of HP1 to the cyclin E promoter. <a href="#52" class="mim-tip-reference" title="Nielsen, S. J., Schneider, R., Bauer, U.-M., Bannister, A. J., Morrison, A., O'Carroll, D., Firestein, R., Cleary, M., Jenuwein, T., Herrera, R. E., Kouzarides, T. <strong>Rb targets histone H3 methylation and HP1 to promoters.</strong> Nature 412: 561-565, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11484059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11484059</a>] [<a href="https://doi.org/10.1038/35087620" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11484059">Nielsen et al. (2001)</a> concluded that the SUV39H1-HP1 complex is not only involved in heterochromatic silencing but also has a role in repression of euchromatic genes by Rb and perhaps other corepressor proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11484059" 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="Dahiya, A., Wong, S., Gonzalo, S., Gavin, M., Dean, D. C. <strong>Linking the Rb and Polycomb pathways.</strong> Molec. Cell 8: 557-568, 2001. Note: Erratum: Molec. Cell 11: 1693-1696, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11583618/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11583618</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00346-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11583618">Dahiya et al. (2001)</a> found that association between RB and Polycomb group (PcG; see <a href="/entry/300227">300227</a>) proteins forms a repressor complex that blocks entry of cells into mitosis. Also, they provided evidence that RB colocalizes with nuclear PcG complexes and is important for association of PcG complexes with nuclear targets. The RB-PcG complex may provide a means to link cell cycle arrest to differentiation events leading to embryonic pattern formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11583618" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The incidence of osteosarcoma is increased 500-fold in patients who inherit mutations in the RB gene. To understand why the RB protein is specifically targeted in osteosarcoma, <a href="#68" class="mim-tip-reference" title="Thomas, D. M., Carty, S. A., Piscopo, D. M., Lee, J.-S., Wang, W.-F., Forrester, W. C., Hinds, P. W. <strong>The retinoblastoma protein acts as a transcriptional coactivator required for osteogenic differentiation.</strong> Molec. Cell 8: 303-316, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11545733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11545733</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00327-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11545733">Thomas et al. (2001)</a> studied its function in osteogenesis. Loss of RB but not p107 (<a href="/entry/116957">116957</a>) or p130 (<a href="/entry/180203">180203</a>) blocked late osteoblast differentiation. RB physically interacted with the osteoblast transcription factor, CBFA1 (<a href="/entry/600211">600211</a>), and associated with osteoblast-specific promoters in vivo in a CBFA1-dependent fashion. Association of RB with CBFA1 and promoter sequences resulted in synergistic transactivation of an osteoblast-specific reporter. This transactivation function was lost in tumor-derived RB mutants, underscoring a potential role in tumor suppression. Thus, RB functions as a direct transcriptional coactivator promoting osteoblast differentiation, which may contribute to the targeting of RB in osteosarcoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11545733" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By yeast 2-hybrid analysis using a human fibroblast cDNA library and protein pull-down assays with human EJ bladder cancer cells and Saos2 osteosarcoma cells, <a href="#43" class="mim-tip-reference" title="Leung, J. K., Berube, N., Venable, S., Ahmed, S., Timchenko, N., Pereira-Smith, O. M. <strong>MRG15 activates the B-myb promoter through formation of a nuclear complex with the retinoblastoma protein and the novel protein PAM14.</strong> J. Biol. Chem. 276: 39171-39178, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11500496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11500496</a>] [<a href="https://doi.org/10.1074/jbc.M103435200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11500496">Leung et al. (2001)</a> showed that MRG15 (MORF4L1; <a href="/entry/607303">607303</a>) interacted with PAM14 (MRFAP1; <a href="/entry/616905">616905</a>) and RB. Deletion analysis showed that the helix-loop-helix and leucine zipper regions of MRG15 were important for interaction with both PAM14 and RB. Immunoprecipitation analysis of EJ cells and human fibroblasts revealed that MRG15, PAM14, and RB were present in a multiprotein complex. Luciferase assays showed that MRG15 blocked RB-induced repression of the BMYB (MYBL2; <a href="/entry/601415">601415</a>) promoter, leading to BMYB promoter activation. <a href="#43" class="mim-tip-reference" title="Leung, J. K., Berube, N., Venable, S., Ahmed, S., Timchenko, N., Pereira-Smith, O. M. <strong>MRG15 activates the B-myb promoter through formation of a nuclear complex with the retinoblastoma protein and the novel protein PAM14.</strong> J. Biol. Chem. 276: 39171-39178, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11500496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11500496</a>] [<a href="https://doi.org/10.1074/jbc.M103435200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11500496">Leung et al. (2001)</a> concluded that MRG15 regulates transcription through interactions with a complex containing RB and PAM14. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11500496" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using immunoprecipitation and immunoblot analyses, <a href="#70" class="mim-tip-reference" title="Tominaga, K., Magee, D. M., Matzuk, M. M., Pereira-Smith, O. M. <strong>PAM14, a novel MRG- and Rb-associated protein, is not required for development and T-cell function in mice.</strong> Molec. Cell. Biol. 24: 8366-8373, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15367658/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15367658</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15367658[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/10.1128/MCB.24.19.8366-8373.2004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15367658">Tominaga et al. (2004)</a> showed that Mrg15 interacted with Pam14 and Rb in mouse cells, similar to findings in human cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15367658" 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="#19" class="mim-tip-reference" title="Fajas, L., Egler, V., Reiter, R., Hansen, J., Kristiansen, K., Debril, M.-B., Miard, S., Auwerx, J. <strong>The retinoblastoma-histone deacetylase 3 complex inhibits PPAR-gamma and adipocyte differentiation.</strong> Dev. Cell 3: 903-910, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12479814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12479814</a>] [<a href="https://doi.org/10.1016/s1534-5807(02)00360-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12479814">Fajas et al. (2002)</a> found that Pparg (<a href="/entry/601487">601487</a>) promoted adipocyte differentiation more efficiently in Rb-deficient mouse embryonic fibroblasts than in Rb-expressing controls. Pparg and Rb coimmunoprecipitated, and the Pparg-Rb complex also contained histone deacetylase-3 (HDAC3; <a href="/entry/605166">605166</a>). Rb recruited Hdac3 to the Pparg-Rb complex, and recruitment attenuated Pparg-mediated gene expression and adipocyte differentiation. Dissociation of the Pparg-Rb-Hdac3 complex by Rb phosphorylation or inhibition of Hdac activity stimulated adipocyte differentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12479814" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Chano, T., Ikegawa, S., Kontani, K., Okabe, H., Baldini, N., Saeki, Y. <strong>Identification of RB1CC1, a novel human gene that can induce RB1 in various human cells.</strong> Oncogene 21: 1295-1298, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11850849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11850849</a>] [<a href="https://doi.org/10.1038/sj.onc.1205178" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11850849">Chano et al. (2002)</a> identified and cloned an RB1-inducible coiled-coil protein (RB1CC1; <a href="/entry/606837">606837</a>) by differential display between a multidrug resistant osteosarcoma cell line and the sensitive parental cell line. By semiquantitative RT-PCR of a panel of cancer cell lines, they observed a close correlation between expression of RB1 and expression of RB1CC1. In addition, they found that exogenous expression of RB1CC1 in 2 leukemia cell lines produced a marked increase in RB1 expression. The induction was found to be due to the activation of the RB1 promoter by RB1CC1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11850849" 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="#23" class="mim-tip-reference" title="Garcia-Cao, M., Gonzalo, S., Dean, D., Blasco, M. A. <strong>A role for the Rb family of proteins in controlling telomere length.</strong> Nature Genet. 32: 415-419, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12379853/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12379853</a>] [<a href="https://doi.org/10.1038/ng1011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12379853">Garcia-Cao et al. (2002)</a> reported a connection between members of the retinoblastoma family of proteins, RB1, RBL1 (<a href="/entry/116957">116957</a>), and RBL2 (<a href="/entry/180203">180203</a>), and the mechanisms that regulate telomere length. In particular, mouse embryonic fibroblasts doubly deficient in Rbl1 and Rbl2 or triply deficient in all 3 genes had markedly elongated telomeres compared with those of wildtype or Rb1-deficient cells. This deregulation of telomere length was not associated with increased telomerase (see <a href="/entry/187270">187270</a>) activity. The abnormal elongated telomeres in doubly or triply deficient cells retained their end-capping function, as shown by the normal frequency of chromosomal fusions. These findings demonstrated a connection between the RB1 family and the control of telomere length in mammalian cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12379853" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Brown, V. D., Gallie, B. L. <strong>The B-domain lysine patch of pRB is required for binding to large T antigen and release of E2F by phosphorylation .</strong> Molec. Cell. Biol. 22: 1390-1401, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11839806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11839806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11839806[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/10.1128/MCB.22.5.1390-1401.2002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11839806">Brown and Gallie (2002)</a> stated that interaction of mouse Rb with E2f on DNA is regulated by accumulation of phosphate groups in the C-terminal domain of Rb. By mutation analysis, they identified a 6-lysine basic patch in the Rb B domain that was necessary for release of Rb from E2f on DNA and for interaction of Rb with SV40 T antigen. <a href="#2" class="mim-tip-reference" title="Brown, V. D., Gallie, B. L. <strong>The B-domain lysine patch of pRB is required for binding to large T antigen and release of E2F by phosphorylation .</strong> Molec. Cell. Biol. 22: 1390-1401, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11839806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11839806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11839806[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/10.1128/MCB.22.5.1390-1401.2002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11839806">Brown and Gallie (2002)</a> suggested that release of E2F from Rb involves a conformational change whereby the C-terminal domain interacts with the B domain following phosphorylation by cyclin E. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11839806" 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>Cellular senescence is a stable form of cell cycle arrest that limits proliferation of damaged cells and may act as a natural barrier to cancer progression. <a href="#51" class="mim-tip-reference" title="Narita, M., Nunez, S., Heard, E., Narita, M., Lin, A. W., Hearn, S. A., Spector, D. L., Hannon, G. J., Lowe, S. W. <strong>Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence.</strong> Cell 113: 703-716, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12809602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12809602</a>] [<a href="https://doi.org/10.1016/s0092-8674(03)00401-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12809602">Narita et al. (2003)</a> described a distinct heterochromatic structure that accumulates in senescent human fibroblasts, designated senescence-associated heterochromatic foci (SAHF). They found that SAHF formation coincides with recruitment of heterochromatin proteins and the RB1 protein to E2F-responsive promoters and is associated with the stable repression of E2F target genes. Both SAHF formation and the silencing of E2F target genes depended on the integrity of the RB pathway and did not occur in reversibly arrested cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12809602" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The RB gene regulates proliferation, cell fate specification, and differentiation in the developing central nervous system. In the postnatal developing mouse retina, <a href="#85" class="mim-tip-reference" title="Zhang, J., Gray, J., Wu, L., Leone, G., Rowan, S., Cepko, C. L., Zhu, X., Craft, C. M., Dyer, M. A. <strong>Rb regulates proliferation and rod photoreceptor development in the mouse retina.</strong> Nature Genet. 36: 351-360, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14991054/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14991054</a>] [<a href="https://doi.org/10.1038/ng1318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14991054">Zhang et al. (2004)</a> found that Rb is expressed in proliferating retinal progenitor cells and differentiating rod photoreceptors. In retinal cell cultures from Rb-null mice and retinal cells from transgenic mice with targeted inactivation of the Rb gene, retinal progenitor cells continued to divide and rods did not mature, suggesting that Rb plays a role in cell proliferation and rod photoreceptor development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14991054" 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="Iavarone, A., King, E. R., Dai, X.-M., Leone, G., Stanley, E. R., Lasorella, A. <strong>Retinoblastoma promotes definitive erythropoiesis by repressing Id2 in fetal liver macrophages.</strong> Nature 432: 1040-1045, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15616565/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15616565</a>] [<a href="https://doi.org/10.1038/nature03068" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15616565">Iavarone et al. (2004)</a> showed that Rb-deficient embryos carry profound abnormalities of fetal liver macrophages that prevent physical interactions with erythroblasts. In contrast, wildtype macrophages bind Rb-deficient erythroblasts and lead to terminal differentiation and enucleation. Loss of Id2 (<a href="/entry/600386">600386</a>), a helix-loop-helix protein that mediates the lethality of Rb-deficient embryos, rescues the defects of Rb-deficient fetal liver macrophages. Rb promotes differentiation of macrophages by opposing the inhibitory functions of Id2 on the transcription factor PU.1 (<a href="/entry/165170">165170</a>), a master regulator of macrophage differentiation. Thus, Rb has a cell-autonomous function in fetal liver macrophages, and restrains Id2 in these cells to implement definitive erythropoiesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15616565" 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="Sekimata, M., Homma, Y. <strong>Regulation of Rb gene expression by an MBD2-interacting zinc finger protein MIZF during myogenic differentiation.</strong> Biochem. Biophys. Res. Commun. 325: 653-659, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15541338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15541338</a>] [<a href="https://doi.org/10.1016/j.bbrc.2004.10.090" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15541338">Sekimata and Homma (2004)</a> developed a mouse myoblast cell line constitutively overexpressing Mizf (<a href="/entry/607099">607099</a>). When switched to differentiation medium, these cells showed decreased expression of Rb and several differentiation markers, and consequently could not differentiate into multinucleated myotubes. <a href="#64" class="mim-tip-reference" title="Sekimata, M., Homma, Y. <strong>Regulation of Rb gene expression by an MBD2-interacting zinc finger protein MIZF during myogenic differentiation.</strong> Biochem. Biophys. Res. Commun. 325: 653-659, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15541338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15541338</a>] [<a href="https://doi.org/10.1016/j.bbrc.2004.10.090" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15541338">Sekimata and Homma (2004)</a> concluded that repression of RB by MIZF is a critical determinant of myogenic differentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15541338" 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="Carreira, S., Goodall, J., Aksan, I., La Rocca, S. A., Galibert, M.-D., Denat, L., Larue, L., Goding, C. R. <strong>Mitf cooperates with Rb1 and activates p21(Cip1) expression to regulate cell cycle progression.</strong> Nature 433: 764-769, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15716956/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15716956</a>] [<a href="https://doi.org/10.1038/nature03269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15716956">Carreira et al. (2005)</a> showed that cooperation between MITF (<a href="/entry/156845">156845</a>) and RB1 potentiates the ability of MITF to activate transcription. <a href="#5" class="mim-tip-reference" title="Carreira, S., Goodall, J., Aksan, I., La Rocca, S. A., Galibert, M.-D., Denat, L., Larue, L., Goding, C. R. <strong>Mitf cooperates with Rb1 and activates p21(Cip1) expression to regulate cell cycle progression.</strong> Nature 433: 764-769, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15716956/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15716956</a>] [<a href="https://doi.org/10.1038/nature03269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15716956">Carreira et al. (2005)</a> suggested that MITF-mediated activation of p21(Cip1) (CDKN1A; <a href="/entry/116899">116899</a>) expression and consequent hypophosphorylation of RB1 contributes to cell cycle exit and activation of the differentiation program. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15716956" 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>Caenorhabditis elegans homologs of the Rb tumor suppressor complex specify cell lineage during development. <a href="#73" class="mim-tip-reference" title="Wang, D., Kennedy, S., Conte, D., Jr., Kim, J. K., Gabel, H. W., Kamath, R. S., Mello, C. C., Ruvkun, G. <strong>Somatic misexpression of germline P granules and enhanced RNA interference in retinoblastoma pathway mutants. (Letter)</strong> Nature 436: 593-597, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16049496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16049496</a>] [<a href="https://doi.org/10.1038/nature04010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16049496">Wang et al. (2005)</a> showed that mutations in Rb pathway components enhanced RNA interference and caused somatic cells to express genes and elaborate perinuclear structures normally limited to germline-specific P granules. Furthermore, particular gene inactivations that disrupted RNA interference (RNAi) reversed the cell lineage transformations of Rb pathway mutants. <a href="#73" class="mim-tip-reference" title="Wang, D., Kennedy, S., Conte, D., Jr., Kim, J. K., Gabel, H. W., Kamath, R. S., Mello, C. C., Ruvkun, G. <strong>Somatic misexpression of germline P granules and enhanced RNA interference in retinoblastoma pathway mutants. (Letter)</strong> Nature 436: 593-597, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16049496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16049496</a>] [<a href="https://doi.org/10.1038/nature04010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16049496">Wang et al. (2005)</a> concluded that mutations in Rb pathway components cause cells to revert to patterns of gene expression normally restricted to germ cells in C. elegans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16049496" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By profiling gene expression in developing mouse vestibular organs, <a href="#59" class="mim-tip-reference" title="Sage, C., Huang, M., Karimi, K., Gutierrez, G., Vollrath, M. A., Zhang, D.-S., Garcia-Anoveros, J., Hinds, P. W., Corwin, J. T., Corey, D. P., Chen, Z.-Y. <strong>Proliferation of functional hair cells in vivo in the absence of the retinoblastoma protein.</strong> Science 307: 1114-1118, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15653467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15653467</a>] [<a href="https://doi.org/10.1126/science.1106642" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15653467">Sage et al. (2005)</a> identified the Rb protein as a candidate regulator of cell cycle exit in hair cells. Differentiated and functional mouse hair cells with a targeted deletion of Rb1 undergo mitosis, divide, and cycle, yet continue to become highly differentiated and functional. Moreover, acute loss of Rb1 in postnatal hair cells caused cell cycle reentry. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15653467" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a yeast 2-hybrid screen to identify proteins that affect RB-mediated gene activation, <a href="#39" class="mim-tip-reference" title="Krutzfeldt, M., Ellis, M., Weekes, D. B., Bull, J. J., Eilers, M., Vivanco, M. M., Sellers, W. R., Mittnacht, S. <strong>Selective ablation of retinoblastoma protein function by the RET finger protein.</strong> Molec. Cell 18: 213-224, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15837424/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15837424</a>] [<a href="https://doi.org/10.1016/j.molcel.2005.03.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15837424">Krutzfeldt et al. (2005)</a> found that RFP (TRIM27; <a href="/entry/602165">602165</a>) strongly reduced the effect of RB on glucocorticoid receptor (GCCR; <a href="/entry/138040">138040</a>)-mediated transcription, but it did not prevent the ability of RB to inhibit E2F-mediated transcription. Mutation analysis showed that RFP interacted with the large pocket of RB in a manner distinct from that of E2F. <a href="#39" class="mim-tip-reference" title="Krutzfeldt, M., Ellis, M., Weekes, D. B., Bull, J. J., Eilers, M., Vivanco, M. M., Sellers, W. R., Mittnacht, S. <strong>Selective ablation of retinoblastoma protein function by the RET finger protein.</strong> Molec. Cell 18: 213-224, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15837424/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15837424</a>] [<a href="https://doi.org/10.1016/j.molcel.2005.03.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15837424">Krutzfeldt et al. (2005)</a> proposed that RFP expression may neutralize the RB-mediated differentiation response while leaving in place E2F-dependent cell cycle regulation and apoptosis protection. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15837424" 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="Laurie, N. A., Donovan, S. L., Shih, C.-S., Zhang, J., Mills, N., Fuller, C., Teunisse, A., Lam, S., Ramos, Y., Mohan, A., Johnson, D., Wilson, M., Rodriguez-Galindo, C., Quarto, M., Francoz, S., Mendrysa, S. M., Guy, R. K., Marine, J.-C., Jochemson, A. G., Dyer, M. A. <strong>Inactivation of the p53 pathway in retinoblastoma.</strong> Nature 444: 61-66, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17080083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17080083</a>] [<a href="https://doi.org/10.1038/nature05194" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17080083">Laurie et al. (2006)</a> showed that the tumor surveillance pathway mediated by ARF (see <a href="/entry/600160">600160</a>), MDM2 (<a href="/entry/164785">164785</a>), MDMX (<a href="/entry/602704">602704</a>), and p53 (<a href="/entry/191170">191170</a>) is activated after loss of RB1 during retinogenesis. RB1-deficient retinoblasts undergo p53-mediated apoptosis and exit the cell cycle. Subsequently, amplification of the MDMX gene and increased expression of MDMX protein are strongly selected for during tumor progression as a mechanism to suppress the p53 response in RB1-deficient retinal cells. <a href="#40" class="mim-tip-reference" title="Laurie, N. A., Donovan, S. L., Shih, C.-S., Zhang, J., Mills, N., Fuller, C., Teunisse, A., Lam, S., Ramos, Y., Mohan, A., Johnson, D., Wilson, M., Rodriguez-Galindo, C., Quarto, M., Francoz, S., Mendrysa, S. M., Guy, R. K., Marine, J.-C., Jochemson, A. G., Dyer, M. A. <strong>Inactivation of the p53 pathway in retinoblastoma.</strong> Nature 444: 61-66, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17080083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17080083</a>] [<a href="https://doi.org/10.1038/nature05194" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17080083">Laurie et al. (2006)</a> concluded that their data provided evidence that the p53 pathway is inactivated in retinoblastoma and that this cancer does not originate from intrinsically death-resistant cells as previously thought. In addition, <a href="#40" class="mim-tip-reference" title="Laurie, N. A., Donovan, S. L., Shih, C.-S., Zhang, J., Mills, N., Fuller, C., Teunisse, A., Lam, S., Ramos, Y., Mohan, A., Johnson, D., Wilson, M., Rodriguez-Galindo, C., Quarto, M., Francoz, S., Mendrysa, S. M., Guy, R. K., Marine, J.-C., Jochemson, A. G., Dyer, M. A. <strong>Inactivation of the p53 pathway in retinoblastoma.</strong> Nature 444: 61-66, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17080083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17080083</a>] [<a href="https://doi.org/10.1038/nature05194" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17080083">Laurie et al. (2006)</a> suggested that their data supported the idea that MDMX is a specific chemotherapeutic target for treating retinoblastoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17080083" 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="#78" class="mim-tip-reference" title="Williams, J. P., Stewart, T., Li, B., Mulloy, R., Dimova, D., Classon, M. <strong>The retinoblastoma protein is required for Ras-induced oncogenic transformation.</strong> Molec. Cell. Biol. 26: 1170-1182, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16449633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16449633</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16449633[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/10.1128/MCB.26.4.1170-1182.2006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16449633">Williams et al. (2006)</a> found that mouse fibroblasts lacking Rb were less susceptible to an oncogenic HRAS (<a href="/entry/190020">190020</a>) allele than wildtype cells. Depletion of RB from HRAS-transformed mouse cells or human tumor cells harboring HRAS pathway mutations inhibited their proliferation and anchorage-independent growth. In contrast to Rb -/- mouse fibroblasts, p107 -/- and p130 -/- fibroblasts were more susceptible to HRAS-mediated transformation than wildtype cells. Moreover, loss of RB in human tumor cells harboring an HRAS mutation resulted in increased expression of p107, and overexpression of p107, but not RB, strongly inhibited proliferation of these tumor cells. <a href="#78" class="mim-tip-reference" title="Williams, J. P., Stewart, T., Li, B., Mulloy, R., Dimova, D., Classon, M. <strong>The retinoblastoma protein is required for Ras-induced oncogenic transformation.</strong> Molec. Cell. Biol. 26: 1170-1182, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16449633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16449633</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16449633[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/10.1128/MCB.26.4.1170-1182.2006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16449633">Williams et al. (2006)</a> concluded that RB and p107 have distinct roles in HRAS-mediated transformation and that p107 has a role as a tumor suppressor in the context of activated HRAS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16449633" 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="#50" class="mim-tip-reference" title="Morris, E. J., Ji, J.-Y., Yang, F., DiStefano, L., Herr, A., Moon, N.-S., Kwon, E.-J., Haigis, K. M., Naar, A. M., Dyson, N. J. <strong>E2F1 represses beta-catenin transcription and is antagonized by both pRB and CDK8.</strong> Nature 455: 552-556, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18794899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18794899</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18794899[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/nature07310" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18794899">Morris et al. (2008)</a> demonstrated that E2F1 (<a href="/entry/189971">189971</a>) is a potent and specific inhibitor of beta-catenin (<a href="/entry/116806">116806</a>)/T cell factor (TCF)-dependent transcription and that this function contributes to E2F1-induced apoptosis. E2F1 deregulation suppresses beta-catenin activity in an adenomatous polyposis coli (APC; <a href="/entry/611731">611731</a>)/glycogen synthase kinase-3 (GSK3; see <a href="/entry/606784">606784</a>)-independent manner, reducing the expression of key beta-catenin targets including c-MYC. This interaction explains why colorectal tumors, which depend on beta-catenin transcription for their abnormal proliferation, keep RB1 intact. Remarkably, E2F1 activity is also repressed by cyclin-dependent kinase-8 (CDK8; <a href="/entry/603184">603184</a>), a colorectal oncoprotein. Elevated levels of CDK8 protect beta-catenin/TCF-dependent transcription from inhibition by E2F1. <a href="#50" class="mim-tip-reference" title="Morris, E. J., Ji, J.-Y., Yang, F., DiStefano, L., Herr, A., Moon, N.-S., Kwon, E.-J., Haigis, K. M., Naar, A. M., Dyson, N. J. <strong>E2F1 represses beta-catenin transcription and is antagonized by both pRB and CDK8.</strong> Nature 455: 552-556, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18794899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18794899</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18794899[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/nature07310" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18794899">Morris et al. (2008)</a> concluded that thus, by retaining RB1 and amplifying CDK8, colorectal tumor cells select conditions that collectively suppress E2F1 and enhance the activity of beta-catenin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18794899" 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="#35" class="mim-tip-reference" title="Hume, A. J., Finkel, J. S., Kamil, J. P., Coen, D. M., Culbertson, M. R., Kalejta, R. F. <strong>Phosphorylation of retinoblastoma protein by viral protein with cyclin-dependent kinase function.</strong> Science 320: 797-799, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18467589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18467589</a>] [<a href="https://doi.org/10.1126/science.1152095" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18467589">Hume et al. (2008)</a> showed that cytomegalovirus UL97 protein, like human cyclin-dependent kinases (see CDK2, <a href="/entry/116953">116953</a>), phosphorylates RB, but does so in a cyclin-independent manner and is poorly inhibited by p21 (CDKN1A; <a href="/entry/116899">116899</a>). <a href="#35" class="mim-tip-reference" title="Hume, A. J., Finkel, J. S., Kamil, J. P., Coen, D. M., Culbertson, M. R., Kalejta, R. F. <strong>Phosphorylation of retinoblastoma protein by viral protein with cyclin-dependent kinase function.</strong> Science 320: 797-799, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18467589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18467589</a>] [<a href="https://doi.org/10.1126/science.1152095" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18467589">Hume et al. (2008)</a> concluded that UL97 is functionally orthologous to human CDK in phosphorylating RB but is immune from normal CDK control mechanisms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18467589" 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>Dgcr8 (<a href="/entry/609030">609030</a>)-knockout mouse embryonic stem (ES) cells lack microRNAs (miRNAs), proliferate slowly, and accumulate in G1 phase of the cell cycle. By screening mouse miRNAs for those that could rescue the growth defect in Dgcr8-knockout mouse ES cells, <a href="#75" class="mim-tip-reference" title="Wang, Y., Baskerville, S., Shenoy, A., Babiarz, J. E., Baehner, L., Blelloch, R. <strong>Embryonic stem cell-specific microRNAs regulate the G1-S transition and promote rapid proliferation.</strong> Nature Genet. 40: 1478-1483, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18978791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18978791</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18978791[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.250" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18978791">Wang et al. (2008)</a> identified a group of related ES cell-specific miRNAs, including several members of the miR290 cluster. Target sites for these miRNAs were identified in the 3-prime UTRs of several inhibitors of the cyclin E-CDK2 pathway, including Cdkn1a, Rb1, Rbl1, Rbl2, and Lats2 (<a href="/entry/604861">604861</a>). Quantitative RT-PCR confirmed increased expression of these genes in Dgcr8-knockout mouse ES cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18978791" 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="#74" class="mim-tip-reference" title="Wang, H., Bauzon, F., Ji, P., Xu, X., Sun, D., Locker, J., Sellers, R. S., Nakayama, K., Nakayama, K. I., Cobrinik, D., Zhu, L. <strong>Skp2 is required for survival of aberrantly proliferating Rb1-deficient cells and for tumorigenesis in Rb1+/- mice.</strong> Nature Genet. 42: 83-88, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19966802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19966802</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19966802[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.498" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19966802">Wang et al. (2010)</a> found that inactivation of Skp2 (<a href="/entry/601436">601436</a>), which is a target of Rb1, completely prevented spontaneous tumorigenesis in pituitaries of Rb1 +/- mice. Skp2 inactivation did not inhibit aberrant proliferation in Rb1-deleted melanotrophs but induced their apoptotic death. Elimination of p27 (<a href="/entry/600778">600778</a>) phosphorylation reproduced the effects of Skp2 knockout. <a href="#74" class="mim-tip-reference" title="Wang, H., Bauzon, F., Ji, P., Xu, X., Sun, D., Locker, J., Sellers, R. S., Nakayama, K., Nakayama, K. I., Cobrinik, D., Zhu, L. <strong>Skp2 is required for survival of aberrantly proliferating Rb1-deficient cells and for tumorigenesis in Rb1+/- mice.</strong> Nature Genet. 42: 83-88, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19966802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19966802</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19966802[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.498" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19966802">Wang et al. (2010)</a> concluded that downregulation of RB1 is tumorigenic due to unregulated SKP2-mediated ubiquitination of phosphorylated p27, followed by p27 degradation and cell cycle progression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19966802" 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>Depending on the differentiation factor and cellular context, the Rb protein can either suppress or promote the transcriptional activity of several master differentiation inducers. For example, Rb protein binds to RUNX2 (<a href="/entry/600211">600211</a>) and potentiates its ability to promote osteogenic differentiation in vitro. In contrast, Rb protein acts with E2F to suppress PPARG (<a href="/entry/601487">601487</a>), the master activator of adipogenesis. Because osteoblasts and adipocytes can both arise from mesenchymal stem cells, these observations suggest that Rb protein might play a role in the choice between these 2 fates. <a href="#4" class="mim-tip-reference" title="Calo, E., Quintero-Estades, J. A., Danielian, P. S., Nedelcu, S., Berman, S. D., Lees, J. A. <strong>Rb regulates fate choice and lineage commitment in vivo.</strong> Nature 466: 1110-1114, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20686481/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20686481</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20686481[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/nature09264" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20686481">Calo et al. (2010)</a> used mouse models to address this hypothesis in mesenchymal tissue development and tumorigenesis and showed that Rb status plays a key role in establishing fate choice between bone and brown adipose tissue in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20686481" 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>Based on genomewide methylation analysis of a patient with multiple imprinting defects, <a href="#37" class="mim-tip-reference" title="Kanber, D., Berulava, T., Ammerpohl, O., Mitter, D., Richter, J., Siebert, R., Horsthemke, B., Lohmann, D., Buiting, K. <strong>The human retinoblastoma gene is imprinted.</strong> PLoS Genet. 5: e1000790, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20041224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20041224</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20041224[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1000790" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20041224">Kanber et al. (2009)</a> identified a differentially methylated CpG island in intron 2 of the RB1 gene. The CpG island is part of a 5-prime truncated, processed pseudogene derived from the KIAA0649 gene (<a href="/entry/614056">614056</a>) on chromosome 9 and corresponds to 2 small CpG islands in the open reading frame of the ancestral gene. It is methylated on the maternal chromosome 13 and acts as a weak promoter for an alternative RB1 transcript on the paternal chromosome 13. In 4 other KIAA0649 pseudogene copies, which are located on chromosome 22, the 2 CpG islands have deteriorated and the CpG dinucleotides are fully methylated. By analyzing allelic RB1 transcript levels in blood cells, as well as in hypermethylated and 5-aza-2-prime-deoxycytidine-treated lymphoblastoid cells, <a href="#37" class="mim-tip-reference" title="Kanber, D., Berulava, T., Ammerpohl, O., Mitter, D., Richter, J., Siebert, R., Horsthemke, B., Lohmann, D., Buiting, K. <strong>The human retinoblastoma gene is imprinted.</strong> PLoS Genet. 5: e1000790, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20041224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20041224</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20041224[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1000790" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20041224">Kanber et al. (2009)</a> found that differential methylation of the CpG island (CpG 85) skews RB1 gene expression in favor of the maternal allele. Thus, <a href="#37" class="mim-tip-reference" title="Kanber, D., Berulava, T., Ammerpohl, O., Mitter, D., Richter, J., Siebert, R., Horsthemke, B., Lohmann, D., Buiting, K. <strong>The human retinoblastoma gene is imprinted.</strong> PLoS Genet. 5: e1000790, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20041224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20041224</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20041224[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1000790" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20041224">Kanber et al. (2009)</a> concluded that RB1 is imprinted in the same direction as CDKN1C (<a href="/entry/600856">600856</a>), which operates upstream of RB1. The imprinting of 2 components of the same pathway indicates that there has been strong evolutionary selection for maternal inhibition of cell proliferation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20041224" 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="#79" class="mim-tip-reference" title="Xu, X. L., Singh, H. P., Wang, L., Qi, D.-L., Poulos, B. K., Abramson, D. H., Jhanwar, S. C., Cobrinik, D. <strong>Rb suppresses human cone-precursor-derived retinoblastoma tumours.</strong> Nature 514: 385-388, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25252974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25252974</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25252974[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/nature13813" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25252974">Xu et al. (2014)</a> showed that postmitotic human cone precursors are uniquely sensitive to RB depletion. RB knockdown induced cone precursor proliferation in prospectively isolated populations and in intact retina. Proliferation followed the induction of E2F-regulated genes, and depended on factors having strong expression in maturing cone precursors and crucial roles in retinoblastoma cell proliferation, including MYCN (<a href="/entry/164840">164840</a>) and MDM2 (<a href="/entry/164785">164785</a>). Proliferation of RB-depleted cones and retinoblastoma cells also depended on the RB-related protein p107 (RBL1; <a href="/entry/116957">116957</a>), SKP2 (<a href="/entry/601436">601436</a>), and a p27 (CDKN1B; <a href="/entry/600778">600778</a>) downregulation associated with cone precursor maturation. Moreover, RB-depleted cone precursors formed tumors in orthotopic xenografts with histologic features and protein expression typical of human retinoblastoma. <a href="#79" class="mim-tip-reference" title="Xu, X. L., Singh, H. P., Wang, L., Qi, D.-L., Poulos, B. K., Abramson, D. H., Jhanwar, S. C., Cobrinik, D. <strong>Rb suppresses human cone-precursor-derived retinoblastoma tumours.</strong> Nature 514: 385-388, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25252974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25252974</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25252974[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/nature13813" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25252974">Xu et al. (2014)</a> concluded that these findings provide a compelling molecular rationale for a cone precursor origin of retinoblastoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25252974" 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 mice, <a href="#72" class="mim-tip-reference" title="Walter, D. M., Yates, T. J., Ruiz-Torres, M., Kim-Kiselak, C., Gudiel, A. A., Deshpande, C., Wang, W. Z., Cicchini, M., Stokes, K. L., Tobias, J. W., Buza, E., Feldser, D. M. <strong>RB constrains lineage fidelity and multiple stages of tumour progression and metastasis.</strong> Nature 569: 423-427, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31043741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31043741</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31043741[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/s41586-019-1172-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31043741">Walter et al. (2019)</a> modeled RB loss during lung adenocarcinoma progression and pathway reactivation in established oncogenic KRAS (<a href="/entry/190070">190070</a>)-driven tumors. They showed that RB loss enables cancer cells to bypass 2 distinct barriers during tumor progression. First, RB loss abrogates the requirement for amplification of the mitogen-activated protein kinase (MAPK; see <a href="/entry/176948">176948</a>) signal during malignant progression. <a href="#72" class="mim-tip-reference" title="Walter, D. M., Yates, T. J., Ruiz-Torres, M., Kim-Kiselak, C., Gudiel, A. A., Deshpande, C., Wang, W. Z., Cicchini, M., Stokes, K. L., Tobias, J. W., Buza, E., Feldser, D. M. <strong>RB constrains lineage fidelity and multiple stages of tumour progression and metastasis.</strong> Nature 569: 423-427, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31043741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31043741</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31043741[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/s41586-019-1172-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31043741">Walter et al. (2019)</a> identified CDK2 (<a href="/entry/116953">116953</a>)-dependent phosphorylation of RB as an effector of MAPK signaling and critical mediator of resistance to inhibition of CDK4 (<a href="/entry/123829">123829</a>) and CDK6 (<a href="/entry/603368">603368</a>). Second, RB inactivation deregulates the expression of cell-state-determining factors, facilitates lineage infidelity, and accelerates the acquisition of metastatic competency. By contrast, reactivation of RB reprograms advanced tumors towards a less metastatic cell state, but is nevertheless unable to halt cancer cell proliferation and tumor growth due to adaptive rewiring of MAPK pathway signaling, which restores a CDK-dependent suppression of RB. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31043741" 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="#82" class="mim-tip-reference" title="Zatulovskiy, E., Zhang, S., Berenson, D. F., Topacio, B. R., Skotheim, J. M. <strong>Cell growth dilutes the cell cycle inhibitor Rb to trigger cell division.</strong> Science 369: 466-471, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32703881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32703881</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32703881[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.aaz6213" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32703881">Zatulovskiy et al. (2020)</a> showed that cell growth during G1 phase of the cell division cycle diluted RB to trigger division in human cells. RB overexpression increased cell size and G1 duration, whereas RB deletion decreased cell size and removed the inverse correlation between cell size at birth and duration of G1 phase. <a href="#82" class="mim-tip-reference" title="Zatulovskiy, E., Zhang, S., Berenson, D. F., Topacio, B. R., Skotheim, J. M. <strong>Cell growth dilutes the cell cycle inhibitor Rb to trigger cell division.</strong> Science 369: 466-471, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32703881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32703881</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32703881[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.aaz6213" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32703881">Zatulovskiy et al. (2020)</a> concluded that RB dilution through cell growth in G1 provides a molecular mechanism that promotes cell size homeostasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32703881" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The restriction (R) point marks the point in the cell cycle when cells become independent of mitogen signaling and CDK2 activity becomes self-sustaining through a feedback loop between cyclin A2/CDK2 and RB1, leading to an irreversible commitment to proliferation. <a href="#9" class="mim-tip-reference" title="Cornwell, J. A., Crncec, A., Afifi, M. M., Tang, K., Amin, R., Cappell, S. D. <strong>Loss of CDK4/6 activity in S/G2 phase leads to cell cycle reversal.</strong> Nature 619: 363-370, 2023. Note: Erratum: Nature 630: E14, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37407814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37407814</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37407814[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/s41586-023-06274-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37407814">Cornwell et al. (2023)</a> demonstrated that mitogen signaling maintained CDK2 activity in S and G2 phases of the cell cycle, and that, in the absence of mitogen signaling, some post-R-point cells exited the cell cycle and entered a G0-like state instead of irreversibly committing to proliferation. Further analysis indicated that mitosis and cell cycle exit were 2 mutually exclusive fates, and that competition between the 2 determined whether cells continued to proliferate or exited the cell cycle. As a result, the decision to proliferate was fully reversible, even when cells were in post-R state, because CDK2 activation and RB1 phosphorylation were reversible in all post-R cells after loss of mitogen signaling. CDK4/CDK6 promoted cyclin A2 synthesis in S/G2, and cyclin A2 stability was the primary contributor to cell cycle exit. Cells were dependent on mitogens and CDK4/CDK6 activity to maintain CDK2 activity and RB1 phosphorylation throughout the cell cycle. The R-point irreversibility phenomenon was observed in the absence of mitogens, because in most cells, the half-life of cyclin A2 was long enough to sustain CDK2 activity throughout G2/M to reach mitosis. The results implied that there is no single point when cells are irreversibly committed to proliferation that can be defined by a single molecular event, but rather that it is determined by the cell's proximity to mitosis, as well as the cyclin A2 level when mitogen signaling is lost. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37407814" 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="#66" class="mim-tip-reference" title="Sivakumaran, T. A., Shen, P., Wall, D. P., Do, B. H., Kucheria, K., Oefner, P. J. <strong>Conservation of the RB1 gene in human and primates.</strong> Hum. Mutat. 25: 396-409, 2005. Note: Erratum: Hum. Mutat. 25: 501 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15776430/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15776430</a>] [<a href="https://doi.org/10.1002/humu.20154" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15776430">Sivakumaran et al. (2005)</a> conducted a comprehensive survey of sequence variation in the RB1 gene in diverse human populations and primates. A study of a wide range of ethnicities and 5 primate species indicated that nucleotide diversity of the coding region was 52 times lower than that of the noncoding regions, indicative of significant sequence conservation. The occurrence of purifying selection was corroborated by phylogeny-based maximum likelihood analysis of the RB1 sequences of human and 5 primates. RB1 displayed extensive linkage disequilibrium over 174 kb, and only 4 unique recombination events, 2 in Africa and 1 each in Europe and Southwest Asia, were observed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15776430" 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>Retinoblastoma</em></strong></p><p>
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<a href="#22" class="mim-tip-reference" title="Fung, Y.-K. T., Murphree, A. L., T'Ang, A., Qian, J., Hinrichs, S. H., Benedict, W. F. <strong>Structural evidence for the authenticity of the human retinoblastoma gene.</strong> Science 236: 1657-1661, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2885916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2885916</a>] [<a href="https://doi.org/10.1126/science.2885916" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2885916">Fung et al. (1987)</a> used a cDNA probe to determine the lesion in retinoblastomas (<a href="/entry/180200">180200</a>). In 16 of 40 retinoblastomas studied with a cDNA probe by <a href="#22" class="mim-tip-reference" title="Fung, Y.-K. T., Murphree, A. L., T'Ang, A., Qian, J., Hinrichs, S. H., Benedict, W. F. <strong>Structural evidence for the authenticity of the human retinoblastoma gene.</strong> Science 236: 1657-1661, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2885916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2885916</a>] [<a href="https://doi.org/10.1126/science.2885916" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2885916">Fung et al. (1987)</a>, a structural change in the RB gene was identifiable, including, in some cases, homozygous internal deletions with corresponding truncated transcripts. An osteosarcoma also had a homozygous internal deletion with a truncated transcript. Possible hotspots for deletion were identified within the RB genomic locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2885916" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Bookstein, R., Lee, E. Y.-H. P., To, H., Young, L.-J., Sery, T. W., Hayes, R. C., Friedmann, T., Lee, W.-H. <strong>Human retinoblastoma susceptibility gene: genomic organization and analysis of heterozygous intragenic deletion mutants.</strong> Proc. Nat. Acad. Sci. 85: 2210-2214, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2895471/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2895471</a>] [<a href="https://doi.org/10.1073/pnas.85.7.2210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2895471">Bookstein et al. (1988)</a> identified at least 20 exons in genomic clones of the RB gene and provisionally numbered them. With a unique sequence probe from intron 1, they detected heterozygous deletions in genomic DNA from 3 retinoblastoma cell lines and genomic rearrangements in fibroblasts from 2 hereditary retinoblastoma patients, indicating that intron 1 includes a frequent site for mutations conferring predisposition to retinoblastoma. Demonstration of a DNA deletion of exons 2-6 from 1 RB allele, as well as the demonstration of other deletions, explains the origin of shortened RB mRNA transcripts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2895471" 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="Dunn, J. M., Phillips, R. A., Zhu, X., Becker, A., Gallie, B. L. <strong>Mutations in the RB1 gene and their effects on transcription.</strong> Molec. Cell. Biol. 9: 4596-4604, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2601691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2601691</a>] [<a href="https://doi.org/10.1128/mcb.9.11.4596-4604.1989" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2601691">Dunn et al. (1989)</a> extended the characterization of mutations in RB1 using RNase protection of RB1 transcripts to locate probable mutations, followed by polymerase chain reaction (PCR) to amplify and sequence the mutant allele. Mutations were identified in 15 of 21 RB tumors; in 8 tumors, the precise error in nucleotide sequence was characterized. Each of 4 germline mutations involved a small deletion or duplication while 3 somatic mutations were point mutations leading to splice alterations and loss of an exon from the mature RB1 mRNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2601691" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By PCR techniques, <a href="#80" class="mim-tip-reference" title="Yandell, D. W., Campbell, T. A., Dayton, S. H., Petersen, R., Walton, D., Little, J. B., McConkie-Rosell, A., Buckley, E., Dryja, T. <strong>Oncogenic point mutations in the human retinoblastoma gene: their application to genetic counseling.</strong> New Eng. J. Med. 321: 1689-1695, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2594029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2594029</a>] [<a href="https://doi.org/10.1056/NEJM198912213212501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2594029">Yandell et al. (1989)</a> demonstrated single nucleotide changes in tumors from 7 patients with simplex retinoblastoma (with no family history of the disease). In 4 patients, the mutation involved only the tumor cells, and in 3 it involved normal somatic cells as well as tumor cells but was not found in either parent. Thus, these 3 represent new germinal mutations. All 3 were C-to-T transitions in the coding strand in the retinoblastoma gene. Two of the 3 occurred at CpG pairs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2594029" 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="Lohmann, D. R., Brandt, B., Hopping, W., Passarge, E., Horsthemke, B. <strong>The spectrum of RB1 germ-line mutations in hereditary retinoblastoma.</strong> Am. J. Hum. Genet. 58: 940-949, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8651278/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8651278</a>]" pmid="8651278">Lohmann et al. (1996)</a> studied 119 patients with hereditary retinoblastoma for germline RB1 mutations. Southern blot hybridization and PCR fragment-length analysis revealed mutations in 48 patients. In the remaining 71 patients, they detected mutations in 51 (72%) by applying heteroduplex analysis, nonisotopic SSCP, and direct sequencing. Rare sequence variants were also found in 4 patients. No region of the RB1 gene was preferentially involved in single base substitutions. Recurrent transitions were observed at most of the 14 CGA codons within the RB1 gene. No mutation was observed in exons 25-27, although this region contains 2 CGA codons. This suggested to the authors that mutations within the 3-prime terminal region of the RB1 gene may not be oncogenic. For the entire series of 119 patients, mutations were identified in 99 (83%). The spectrum comprised 15% large deletions, 26% small length alterations, and 42% base substitutions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8651278" 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="Harbour, J. W. <strong>Molecular basis of low-penetrance retinoblastoma.</strong> Arch. Ophthal. 119: 1699-1704, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11709023/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11709023</a>] [<a href="https://doi.org/10.1001/archopht.119.11.1699" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11709023">Harbour (2001)</a> stated that recent advances in understanding of the structure and function of the RB protein provided insights into the molecular basis of low-penetrance retinoblastoma. Low-penetrance retinoblastoma mutations either cause a reduction in the amount of normal RB that is produced (class 1 mutations) or result in a partially functional mutant RB (class 2 mutations). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11709023" 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="#61" class="mim-tip-reference" title="Sampieri, K., Hadjistilianou, T., Mari, F., Speciale, C., Mencarelli, M. A., Cetta, F., Manoukian, S., Peissel, B., Giachino, D., Pasini, B., Acquaviva, A., Caporossi, A., Frezzotti, R., Renieri, A., Bruttini, M. <strong>Mutational screening of the RB1 gene in Italian patients with retinoblastoma reveals 11 novel mutations.</strong> J. Hum. Genet. 51: 209-216, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16463005/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16463005</a>] [<a href="https://doi.org/10.1007/s10038-005-0348-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16463005">Sampieri et al. (2006)</a> identified mutations in the RB1 gene in 13 (37%) of 35 unrelated Italian patients with retinoblastoma. Mutations were identified in 6 of 9 familial cases and 7 of 26 sporadic cases. Eleven of the 13 mutations were novel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16463005" 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="#84" class="mim-tip-reference" title="Zhang, J., Benavente, C. A., McEvoy, J., Flores-Otero, J., Ding, L., Chen, X., Ulyanov, A., Wu, G., Wilson, M., Wang, J., Brennan, R., Rusch, M., and 24 others. <strong>A novel retinoblastoma therapy from genomic and epigenetic analyses.</strong> Nature 481: 329-334, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22237022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22237022</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22237022[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/nature10733" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22237022">Zhang et al. (2012)</a> showed that the retinoblastoma genome is stable, but that multiple cancer pathways can be epigenetically deregulated. To identify the mutations that cooperate with RB1 loss in retinoblastoma, <a href="#84" class="mim-tip-reference" title="Zhang, J., Benavente, C. A., McEvoy, J., Flores-Otero, J., Ding, L., Chen, X., Ulyanov, A., Wu, G., Wilson, M., Wang, J., Brennan, R., Rusch, M., and 24 others. <strong>A novel retinoblastoma therapy from genomic and epigenetic analyses.</strong> Nature 481: 329-334, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22237022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22237022</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22237022[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/nature10733" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22237022">Zhang et al. (2012)</a> performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. <a href="#84" class="mim-tip-reference" title="Zhang, J., Benavente, C. A., McEvoy, J., Flores-Otero, J., Ding, L., Chen, X., Ulyanov, A., Wu, G., Wilson, M., Wang, J., Brennan, R., Rusch, M., and 24 others. <strong>A novel retinoblastoma therapy from genomic and epigenetic analyses.</strong> Nature 481: 329-334, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22237022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22237022</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22237022[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/nature10733" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22237022">Zhang et al. (2012)</a> then evaluated the role of RB1 in genome stability and considered nongenetic mechanisms of cancer pathway deregulation. For example, the protooncogene SYK (<a href="/entry/600085">600085</a>) is upregulated in retinoblastoma and is required for tumor cell survival. Targeting SYK with a small molecule inhibitor induced retinoblastoma tumor cell death in vitro and in vivo. Thus, <a href="#84" class="mim-tip-reference" title="Zhang, J., Benavente, C. A., McEvoy, J., Flores-Otero, J., Ding, L., Chen, X., Ulyanov, A., Wu, G., Wilson, M., Wang, J., Brennan, R., Rusch, M., and 24 others. <strong>A novel retinoblastoma therapy from genomic and epigenetic analyses.</strong> Nature 481: 329-334, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22237022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22237022</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22237022[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/nature10733" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22237022">Zhang et al. (2012)</a> concluded that retinoblastomas may develop quickly as a result of the epigenetic deregulation of key cancer pathways as a direct or indirect result of RB1 loss. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22237022" 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>Small-Cell Lung Cancer</em></strong></p><p>
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<a href="#81" class="mim-tip-reference" title="Yokota, J., Akiyama, T., Fung, Y.-K. T., Benedict, W. F., Namba, Y., Hanaoka, M., Wada, M., Terasaki, T., Shimosato, Y., Sugimura, T., Terada, M. <strong>Altered expression of the retinoblastoma (RB) gene in small-cell carcinoma of the lung.</strong> Oncogene 3: 471-475, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2856251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2856251</a>]" pmid="2856251">Yokota et al. (1988)</a> found markedly reduced amounts of RB transcript in some small-cell carcinomas (<a href="/entry/182280">182280</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2856251" 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="#28" class="mim-tip-reference" title="Hensel, C., Hsieh, C.-L., Lee, W.-H., Pam-Lee, E., Gazdar, A., Sakaguchi, A. Y., Naylor, S. L. <strong>Allele loss and lack of expression of the RB-1 locus in small cell lung cancer. (Abstract)</strong> Am. J. Hum. Genet. 43: A25, 1988."None>Hensel et al. (1988)</a> found that all 3 patients with retinoblastoma whose DNA was heterozygous for a RFLP detected by an RB1 probe showed loss of 1 allele in DNA from small-cell lung cancer tissue.</p><p><a href="#25" class="mim-tip-reference" title="Harbour, J. W., Lai, S.-L., Whang-Peng, J., Gazdar, A. F., Minna, J. D., Kaye, F. J. <strong>Abnormalities in structure and expression of the human retinoblastoma gene in SCLC.</strong> Science 241: 353-357, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2838909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2838909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=2838909[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.2838909" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2838909">Harbour et al. (1988)</a> found structural abnormalities of the RB gene in 1 of 8 primary small-cell lung cancer tumors, in 4 of 22 small-cell lung cancer cell lines, and in 1 of 4 pulmonary carcinoid lines. RB mRNA was absent in 60% of SCLC lines and in 75% of pulmonary carcinoid lines, including all samples with DNA abnormalities. In contrast, RB transcripts were found in 90% of non-SCLC lines and in all normal human lung. It is of interest that both SCLC and pulmonary carcinoids are neuroendocrine tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2838909" 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="#32" class="mim-tip-reference" title="Horowitz, J. M., Park, S.-H., Bogenmann, E., Cheng, J.-C., Yandell, D. W., Kaye, F. J., Minna, J. D., Dryja, T. P., Weinberg, R. A. <strong>Frequent inactivation of the retinoblastoma anti-oncogene is restricted to a subset of human tumor cells.</strong> Proc. Nat. Acad. Sci. 87: 2775-2779, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2181449/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2181449</a>] [<a href="https://doi.org/10.1073/pnas.87.7.2775" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2181449">Horowitz et al. (1990)</a> found that inactivation of the retinoblastoma protein, which is universal in retinoblastoma cells, is present in most small-cell lung cancers and in one-third of bladder cancers but is infrequent in other human tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2181449" 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>Metastatic Cancer</em></strong></p><p>
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<a href="#58" class="mim-tip-reference" title="Robinson, D. R., Wu, Y.-M., Lonigro, R. J., Vats, P., Cobain, E., Everett, J., Cao, X., Rabban, E., Kumar-Sinha, C., Raymond, V., Schuetze, S., Alva, A., and 21 others. <strong>Integrative clinical genomics of metastatic cancer.</strong> Nature 548: 297-303, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28783718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28783718</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28783718[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/nature23306" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28783718">Robinson et al. (2017)</a> performed whole-exome and transcriptome sequencing of 500 adult patients with metastatic solid tumors of diverse lineage and biopsy site. The most prevalent genes somatically altered in metastatic cancer included TP53 (<a href="/entry/191170">191170</a>), CDKN2A (<a href="/entry/600160">600160</a>), PTEN (<a href="/entry/601728">601728</a>), PIK3CA (<a href="/entry/171834">171834</a>), and RB1. Putative pathogenic germline variants were present in 12.2% of cases, of which 75% were related to defects in DNA repair. RNA sequencing complemented DNA sequencing to identify gene fusions, pathway activation, and immune profiling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28783718" 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="allelicVariants" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<span href="#mimAllelicVariantsFold" id="mimAllelicVariantsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimAllelicVariantsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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</span>
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<strong>28 Selected Examples</a>):</strong>
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</span>
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<p />
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</div>
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<a href="/allelicVariants/614041" class="btn btn-default" role="button"> Table View </a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=614041[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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<p />
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<a id="0001" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0001 RETINOBLASTOMA, SOMATIC</strong>
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</h4>
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RB1, 1-BP DEL, 2657G
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776779 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776779;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=rs587776779" 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=rs587776779" 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=RCV000013944 OR RCV002426500" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013944, RCV002426500" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013944...</a>
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<span class="mim-text-font">
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<p>In a tumor from a patient (RB-2) with bilateral retinoblastoma (<a href="/entry/180200">180200</a>), <a href="#80" class="mim-tip-reference" title="Yandell, D. W., Campbell, T. A., Dayton, S. H., Petersen, R., Walton, D., Little, J. B., McConkie-Rosell, A., Buckley, E., Dryja, T. <strong>Oncogenic point mutations in the human retinoblastoma gene: their application to genetic counseling.</strong> New Eng. J. Med. 321: 1689-1695, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2594029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2594029</a>] [<a href="https://doi.org/10.1056/NEJM198912213212501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2594029">Yandell et al. (1989)</a> identified heterozygosity for a 1-bp deletion (2657delG) in exon 24 (which codes for amino acid 840) in the RB1 gene, which caused a frameshift and a new stop codon in exon 25. This was a somatic mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2594029" 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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<h4>
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<span class="mim-font">
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<strong>.0002 RETINOBLASTOMA, 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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<div style="float: left;">
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RB1, IVS19, T-C, +2
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776780 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776780;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=rs587776780" 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=rs587776780" 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=RCV000013945" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013945" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013945</a>
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</span>
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</div>
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<span class="mim-text-font">
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<p>In a tumor from a patient (RB-88) with unilateral retinoblastoma (<a href="/entry/180200">180200</a>), <a href="#80" class="mim-tip-reference" title="Yandell, D. W., Campbell, T. A., Dayton, S. H., Petersen, R., Walton, D., Little, J. B., McConkie-Rosell, A., Buckley, E., Dryja, T. <strong>Oncogenic point mutations in the human retinoblastoma gene: their application to genetic counseling.</strong> New Eng. J. Med. 321: 1689-1695, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2594029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2594029</a>] [<a href="https://doi.org/10.1056/NEJM198912213212501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2594029">Yandell et al. (1989)</a> identified a change of GT-to-GC at the first 2 nucleotides in the intron following exon 19 in the RB1 gene. Loss of the splice-donor site prevented normal splicing. The mutation was not found in the leukocytes of the patient or in the parents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2594029" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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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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<a id="0003" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0003 RETINOBLASTOMA</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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<div style="float: left;">
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RB1, ARG445TER
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</div>
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</span>
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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> rs3092891 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3092891;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/rs3092891?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=rs3092891" 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=rs3092891" 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=RCV000013946 OR RCV000492544 OR RCV002496351 OR RCV002508188" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013946, RCV000492544, RCV002496351, RCV002508188" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013946...</a>
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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 the tumor of a patient (RB-74) with bilateral retinoblastoma (<a href="/entry/180200">180200</a>), <a href="#80" class="mim-tip-reference" title="Yandell, D. W., Campbell, T. A., Dayton, S. H., Petersen, R., Walton, D., Little, J. B., McConkie-Rosell, A., Buckley, E., Dryja, T. <strong>Oncogenic point mutations in the human retinoblastoma gene: their application to genetic counseling.</strong> New Eng. J. Med. 321: 1689-1695, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2594029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2594029</a>] [<a href="https://doi.org/10.1056/NEJM198912213212501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2594029">Yandell et al. (1989)</a> identified heterozygosity for a C-to-T transition at basepair 1462 in exon 14 of the RB1 gene, resulting in an arg445-to-ter substitution. This was a de novo germline mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2594029" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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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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<a id="0004" class="mim-anchor"></a>
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<h4>
|
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<span class="mim-font">
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<strong>.0004 RETINOBLASTOMA</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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<div style="float: left;">
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RB1, SER567LEU
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137853292 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853292;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=rs137853292" 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=rs137853292" 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=RCV000013947 OR RCV004700228" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013947, RCV004700228" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013947...</a>
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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 the tumor from a patient (RB-104) with bilateral retinoblastoma (<a href="/entry/180200">180200</a>), <a href="#80" class="mim-tip-reference" title="Yandell, D. W., Campbell, T. A., Dayton, S. H., Petersen, R., Walton, D., Little, J. B., McConkie-Rosell, A., Buckley, E., Dryja, T. <strong>Oncogenic point mutations in the human retinoblastoma gene: their application to genetic counseling.</strong> New Eng. J. Med. 321: 1689-1695, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2594029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2594029</a>] [<a href="https://doi.org/10.1056/NEJM198912213212501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2594029">Yandell et al. (1989)</a> identified a 1838C-T transition in exon 18 of the RB1 gene, resulting in a ser567-to-leu substitution. This represented homozygosity for a new germline mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2594029" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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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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<a id="0005" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0005 RETINOBLASTOMA</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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<div style="float: left;">
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RB1, ARG787TER
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137853293 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853293;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=rs137853293" 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=rs137853293" 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=RCV000013948 OR RCV000492108 OR RCV000760351 OR RCV005007842" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013948, RCV000492108, RCV000760351, RCV005007842" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013948...</a>
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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 the tumor of a patient (RB-53) with bilateral retinoblastoma (<a href="/entry/180200">180200</a>), <a href="#80" class="mim-tip-reference" title="Yandell, D. W., Campbell, T. A., Dayton, S. H., Petersen, R., Walton, D., Little, J. B., McConkie-Rosell, A., Buckley, E., Dryja, T. <strong>Oncogenic point mutations in the human retinoblastoma gene: their application to genetic counseling.</strong> New Eng. J. Med. 321: 1689-1695, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2594029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2594029</a>] [<a href="https://doi.org/10.1056/NEJM198912213212501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2594029">Yandell et al. (1989)</a> identified a heterozygous 2498C-T transition in exon 23 of the RB1 gene, resulting in an arg787-to-ter substitution. This represented a new germline mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2594029" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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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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<a id="0006" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0006 RETINOBLASTOMA, 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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<div style="float: left;">
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RB1, 1-BP DEL, 2381G
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776781 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776781;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=rs587776781" 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=rs587776781" 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=RCV000013949" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013949" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013949</a>
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<p>In the tumor of a patient (RB-45) with unilateral retinoblastoma (<a href="/entry/180200">180200</a>), <a href="#80" class="mim-tip-reference" title="Yandell, D. W., Campbell, T. A., Dayton, S. H., Petersen, R., Walton, D., Little, J. B., McConkie-Rosell, A., Buckley, E., Dryja, T. <strong>Oncogenic point mutations in the human retinoblastoma gene: their application to genetic counseling.</strong> New Eng. J. Med. 321: 1689-1695, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2594029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2594029</a>] [<a href="https://doi.org/10.1056/NEJM198912213212501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2594029">Yandell et al. (1989)</a> identified a 1-bp deletion (2381delG) in exon 22 of the RB1 gene, which led to a frameshift and creation of a new stop codon close by in exon 22. This was a somatic mutation present in heterozygous state in the tumor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2594029" 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="0007" class="mim-anchor"></a>
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<strong>.0007 RETINOBLASTOMA, SOMATIC</strong>
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RB1, IVS10, G-T, +1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776782 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776782;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=rs587776782" 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=rs587776782" 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=RCV000013950 OR RCV002399322" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013950, RCV002399322" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013950...</a>
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</span>
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<span class="mim-text-font">
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<p>In the tumor from a patient (RB-119) with retinoblastoma (<a href="/entry/180200">180200</a>), <a href="#80" class="mim-tip-reference" title="Yandell, D. W., Campbell, T. A., Dayton, S. H., Petersen, R., Walton, D., Little, J. B., McConkie-Rosell, A., Buckley, E., Dryja, T. <strong>Oncogenic point mutations in the human retinoblastoma gene: their application to genetic counseling.</strong> New Eng. J. Med. 321: 1689-1695, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2594029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2594029</a>] [<a href="https://doi.org/10.1056/NEJM198912213212501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2594029">Yandell et al. (1989)</a> identified a G-to-T transversion in the first nucleotide in the intron following exon 10, which led to loss of a splice/donor site and prevented normal splicing. The mutation was somatic and heterozygous in the tumor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2594029" 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="0008" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0008 RETINOBLASTOMA</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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<div style="float: left;">
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RB1, ARG358TER
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121913301 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913301;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=rs121913301" 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=rs121913301" 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=RCV000013951 OR RCV000492492 OR RCV000725187 OR RCV004668727" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013951, RCV000492492, RCV000725187, RCV004668727" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013951...</a>
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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 cell line RB-W24 from a patient with retinoblastoma (<a href="/entry/180200">180200</a>), <a href="#80" class="mim-tip-reference" title="Yandell, D. W., Campbell, T. A., Dayton, S. H., Petersen, R., Walton, D., Little, J. B., McConkie-Rosell, A., Buckley, E., Dryja, T. <strong>Oncogenic point mutations in the human retinoblastoma gene: their application to genetic counseling.</strong> New Eng. J. Med. 321: 1689-1695, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2594029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2594029</a>] [<a href="https://doi.org/10.1056/NEJM198912213212501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2594029">Yandell et al. (1989)</a> identified a 1119C-T transition in exon 11 of the RB1 gene, resulting in an arg358-to-ter substitution. <a href="#80" class="mim-tip-reference" title="Yandell, D. W., Campbell, T. A., Dayton, S. H., Petersen, R., Walton, D., Little, J. B., McConkie-Rosell, A., Buckley, E., Dryja, T. <strong>Oncogenic point mutations in the human retinoblastoma gene: their application to genetic counseling.</strong> New Eng. J. Med. 321: 1689-1695, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2594029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2594029</a>] [<a href="https://doi.org/10.1056/NEJM198912213212501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2594029">Yandell et al. (1989)</a> could not characterize this mutation because normal somatic tissue was not available for study. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2594029" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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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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<a id="0009" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0009 BLADDER CANCER, 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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<div style="float: left;">
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RB1, IVS20, A-G, -2
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1593538130 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1593538130;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=rs1593538130" 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=rs1593538130" 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=RCV000013952 OR RCV001229630 OR RCV004948134" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013952, RCV001229630, RCV004948134" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013952...</a>
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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 bladder cancer (<a href="/entry/109800">109800</a>) tumor designated J82, <a href="#31" class="mim-tip-reference" title="Horowitz, J. M., Park, S. H., Yandell, D. W., Weinberg, R. A. <strong>Involvement of the retinoblastoma gene in the genesis of various human tumors. In: Kavenee, W.; Hastie, N.; Stanbridge, E. (eds.): Recessive Oncogenes and Tumor Suppression: Current Communications in Molecular Biology.</strong> Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press (pub.) 1989. Pp. 101-108."None>Horowitz et al. (1989)</a> found an A-to-G transition in the next to the last nucleotide in the intron 5-prime to exon 21 in the RB1 gene. Loss of splice-acceptor site prevented normal splicing.</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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<a id="0010" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0010 SMALL CELL CANCER OF THE LUNG, 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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<div style="float: left;">
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RB1, GLU748TER
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121913297 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913297;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=rs121913297" 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=rs121913297" 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=RCV000013953 OR RCV002272016" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013953, RCV002272016" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013953...</a>
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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 small-cell lung cancer tumor (<a href="/entry/182280">182280</a>) designated H69, <a href="#80" class="mim-tip-reference" title="Yandell, D. W., Campbell, T. A., Dayton, S. H., Petersen, R., Walton, D., Little, J. B., McConkie-Rosell, A., Buckley, E., Dryja, T. <strong>Oncogenic point mutations in the human retinoblastoma gene: their application to genetic counseling.</strong> New Eng. J. Med. 321: 1689-1695, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2594029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2594029</a>] [<a href="https://doi.org/10.1056/NEJM198912213212501" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2594029">Yandell et al. (1989)</a> identified a 2379G-T transversion in exon 22 of the RB1 gene, resulting in a glu748-to-ter substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2594029" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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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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<a id="0011" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0011 RETINOBLASTOMA, 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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<div style="float: left;">
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RB1, IVS12, G-A, +1
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</div>
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</span>
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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> rs587776783 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776783;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/rs587776783?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=rs587776783" 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=rs587776783" 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=RCV000114724 OR RCV000492136 OR RCV000763334 OR RCV003460796" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000114724, RCV000492136, RCV000763334, RCV003460796" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000114724...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 unrelated patients with unilateral and unifocal retinoblastoma (RB571, RB600) (<a href="/entry/180200">180200</a>), <a href="#18" class="mim-tip-reference" title="Dunn, J. M., Phillips, R. A., Zhu, X., Becker, A., Gallie, B. L. <strong>Mutations in the RB1 gene and their effects on transcription.</strong> Molec. Cell. Biol. 9: 4596-4604, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2601691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2601691</a>] [<a href="https://doi.org/10.1128/mcb.9.11.4596-4604.1989" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2601691">Dunn et al. (1989)</a> found identical somatic point mutations resulting in loss of exon 12. A frameshift introduced by the loss of exon 12 resulted in a truncated protein of 379 amino acids. A G-to-A transition at the splice donor site of exon 12 was responsible for aberrant splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2601691" 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="0012" class="mim-anchor"></a>
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<strong>.0012 RETINOBLASTOMA</strong>
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RB1, 5-BP DEL, EX8
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013955" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013955" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013955</a>
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<p>By RNase protection of the RB1 mRNA and sequencing of the PCR-cDNA in a patient (RB429) with bilateral retinoblastoma (<a href="/entry/180200">180200</a>). <a href="#18" class="mim-tip-reference" title="Dunn, J. M., Phillips, R. A., Zhu, X., Becker, A., Gallie, B. L. <strong>Mutations in the RB1 gene and their effects on transcription.</strong> Molec. Cell. Biol. 9: 4596-4604, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2601691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2601691</a>] [<a href="https://doi.org/10.1128/mcb.9.11.4596-4604.1989" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2601691">Dunn et al. (1989)</a> identified a mutation in the RB1 gene: a 5-bp deletion in exon 8 causing a frameshift and a new termination codon in exon 8. The predicted truncated protein would contain 268 amino acids. <a href="#18" class="mim-tip-reference" title="Dunn, J. M., Phillips, R. A., Zhu, X., Becker, A., Gallie, B. L. <strong>Mutations in the RB1 gene and their effects on transcription.</strong> Molec. Cell. Biol. 9: 4596-4604, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2601691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2601691</a>] [<a href="https://doi.org/10.1128/mcb.9.11.4596-4604.1989" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2601691">Dunn et al. (1989)</a> could not confirm that this was a germline mutation because constitutional cells from the patient were not available for study. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2601691" 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>.0013 RETINOBLASTOMA</strong>
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RB1, 55-BP DUP, EX10
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1555285429 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555285429;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=rs1555285429" 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=rs1555285429" 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=RCV000013956" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013956" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013956</a>
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<p>In the tumor of a patient (RB538) with retinoblastoma (<a href="/entry/180200">180200</a>), <a href="#18" class="mim-tip-reference" title="Dunn, J. M., Phillips, R. A., Zhu, X., Becker, A., Gallie, B. L. <strong>Mutations in the RB1 gene and their effects on transcription.</strong> Molec. Cell. Biol. 9: 4596-4604, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2601691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2601691</a>] [<a href="https://doi.org/10.1128/mcb.9.11.4596-4604.1989" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2601691">Dunn et al. (1989)</a> identified a 55-bp duplication within exon 10 of the RB1 gene. A frameshift resulted in a new termination codon at position 346. This was a germline mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2601691" 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="0014" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0014 RETINOBLASTOMA</strong>
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</h4>
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RB1, 10-BP DEL, EX18
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776784 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776784;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=rs587776784" 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=rs587776784" 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=RCV000013957" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013957" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013957</a>
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</span>
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<span class="mim-text-font">
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<p>In the tumor of a patient (RB543) with retinoblastoma (<a href="/entry/180200">180200</a>), <a href="#18" class="mim-tip-reference" title="Dunn, J. M., Phillips, R. A., Zhu, X., Becker, A., Gallie, B. L. <strong>Mutations in the RB1 gene and their effects on transcription.</strong> Molec. Cell. Biol. 9: 4596-4604, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2601691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2601691</a>] [<a href="https://doi.org/10.1128/mcb.9.11.4596-4604.1989" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2601691">Dunn et al. (1989)</a> identified a 10-bp deletion within exon 18 of the RB1 gene, causing a frameshift and a new termination codon. The predicted truncated protein would contain 586 amino acids. This was a germline mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2601691" 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="0015" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0015 RETINOBLASTOMA</strong>
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</h4>
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RB1, 9-BP DEL, EX19
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776785 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776785;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=rs587776785" 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=rs587776785" 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=RCV000013958" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013958" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013958</a>
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</span>
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<div>
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<span class="mim-text-font">
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<p>In tumor RB470B from a patient (RB570) with retinoblastoma (<a href="/entry/180200">180200</a>), <a href="#18" class="mim-tip-reference" title="Dunn, J. M., Phillips, R. A., Zhu, X., Becker, A., Gallie, B. L. <strong>Mutations in the RB1 gene and their effects on transcription.</strong> Molec. Cell. Biol. 9: 4596-4604, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2601691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2601691</a>] [<a href="https://doi.org/10.1128/mcb.9.11.4596-4604.1989" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2601691">Dunn et al. (1989)</a> demonstrated a 9-bp deletion in exon 19 of the RB1 gene, leading to a TAA termination codon. The predicted truncated protein would have 649 amino acids. This was a germline mutation. Different somatic mutations (<a href="#0016">614041.0016</a>) were identified in 4 different tumors from this patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2601691" 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="0016" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0016 RETINOBLASTOMA, SOMATIC</strong>
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</span>
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</h4>
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RB1, EX22DEL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776786 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776786;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=rs587776786" 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=rs587776786" 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=RCV000013959" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013959" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013959</a>
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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 patient RB570 with bilateral retinoblastoma who carried a 9-bp deletion in exon 19 of the RB1 gene as the germline mutation (<a href="#0015">614041.0015</a>), <a href="#18" class="mim-tip-reference" title="Dunn, J. M., Phillips, R. A., Zhu, X., Becker, A., Gallie, B. L. <strong>Mutations in the RB1 gene and their effects on transcription.</strong> Molec. Cell. Biol. 9: 4596-4604, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2601691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2601691</a>] [<a href="https://doi.org/10.1128/mcb.9.11.4596-4604.1989" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2601691">Dunn et al. (1989)</a> found a different somatic mutation in each of 4 separate tumors studied. These were 2 different LOH ('loss of heterozygosity') mutations, as indicated by RFLP studies, deletion of exon 22, and a tumor in which the exact nature of the change was not determined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2601691" 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>
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<br />
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<div>
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<a id="0017" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0017 RETINOBLASTOMA</strong>
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</span>
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</h4>
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</div>
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RB1, 189G-T, PROMOTER MUTATION
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906520 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906520;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=rs387906520" 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=rs387906520" 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=RCV000013960" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013960" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013960</a>
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<p><a href="#60" class="mim-tip-reference" title="Sakai, T., Ohtani, N., McGee, T. L., Robbins, P. D., Dryja, T. P. <strong>Oncogenic germ-line mutations in Sp1 and ATF sites in the human retinoblastoma gene.</strong> Nature 353: 83-86, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1881452/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1881452</a>] [<a href="https://doi.org/10.1038/353083a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1881452">Sakai et al. (1991)</a> identified 2 mutations in the 5-prime region of the RB gene in patients with retinoblastoma (<a href="/entry/180200">180200</a>). One was a G-to-T transversion 189 bp 5-prime to the initiating methionine codon; the second was a G-to-A transition 198 bp upstream of the initiating methionine codon (<a href="#0018">614041.0018</a>). The penetrance of these mutations appeared to be low; both carriers in 1 family had only unilateral retinoblastoma, and there were at least 3 obligate carriers who had no retinoblastoma in the second family. The mutation in the first family was within a sequence homologous to the consensus sequence for ATF, a transcription factor related or identical to CREB1 (<a href="/entry/123810">123810</a>). The second mutation was within a sequence similar to that recognized by SP1 (<a href="/entry/189906">189906</a>), a transcription factor with a zinc finger DNA-binding domain. <a href="#60" class="mim-tip-reference" title="Sakai, T., Ohtani, N., McGee, T. L., Robbins, P. D., Dryja, T. P. <strong>Oncogenic germ-line mutations in Sp1 and ATF sites in the human retinoblastoma gene.</strong> Nature 353: 83-86, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1881452/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1881452</a>] [<a href="https://doi.org/10.1038/353083a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1881452">Sakai et al. (1991)</a> demonstrated that these natural mutants did not bind the transcription factors mentioned. The incomplete penetrance of the mutations may be related to the fact that the mutations result in a quantitative decrease in the expression of the RB gene, rather than in its complete inactivity. To develop into a retinoblastoma, it may be necessary for the retinal cell carrying one of these mutations to acquire a second, complete loss-of-function mutation of the homologous normal allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1881452" 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">rs387906521 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906521;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=rs387906521" 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=rs387906521" 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=RCV000013961 OR RCV000492684" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013961, RCV000492684" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013961...</a>
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<p>See <a href="#0017">614041.0017</a> and <a href="#60" class="mim-tip-reference" title="Sakai, T., Ohtani, N., McGee, T. L., Robbins, P. D., Dryja, T. P. <strong>Oncogenic germ-line mutations in Sp1 and ATF sites in the human retinoblastoma gene.</strong> Nature 353: 83-86, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1881452/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1881452</a>] [<a href="https://doi.org/10.1038/353083a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1881452">Sakai et al. (1991)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1881452" 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> rs137853294 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853294;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/rs137853294?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=rs137853294" 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=rs137853294" 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=RCV000013962 OR RCV000492717 OR RCV000763335 OR RCV000790652 OR RCV004813036" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013962, RCV000492717, RCV000763335, RCV000790652, RCV004813036" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013962...</a>
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<p>In 2 families with an unusual low-penetrance phenotype of retinoblastoma (<a href="/entry/180200">180200</a>), with many individuals carrying the gene being unaffected, unilaterally affected, or with evidence of spontaneously regressed tumors, <a href="#53" class="mim-tip-reference" title="Onadim, Z., Hogg, A., Baird, P. N., Cowell, J. K. <strong>Oncogenic point mutations in exon 20 of the RB1 gene in families showing incomplete penetrance and mild expression of the retinoblastoma phenotype.</strong> Proc. Nat. Acad. Sci. 89: 6177-6181, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1352883/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1352883</a>] [<a href="https://doi.org/10.1073/pnas.89.13.6177" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1352883">Onadim et al. (1992)</a> found mutations in exon 20 of RB1. (Also see <a href="#0020">614041.0020</a>.) In 1 family, a C-to-T transition in codon 661 converted an arginine (CGG) to tryptophan (TGG) codon. The incomplete penetrance might indicate that this single amino acid change modified protein structure/function such that tumorigenesis was not inevitable. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1352883" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Cowell, J. K., Bia, B. <strong>A novel missense mutation in patients from a retinoblastoma pedigree showing only mild expression of the tumor phenotype.</strong> Oncogene 16: 3211-3213, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9671401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9671401</a>] [<a href="https://doi.org/10.1038/sj.onc.1201833" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9671401">Cowell and Bia (1998)</a> pointed out that <a href="#45" class="mim-tip-reference" title="Lohmann, D. R., Brandt, B., Hopping, W., Passarge, E., Horsthemke, B. <strong>Spectrum of small length germline mutations in the RB1 gene.</strong> Hum. Molec. Genet. 3: 2187-2193, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7881418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7881418</a>] [<a href="https://doi.org/10.1093/hmg/3.12.2187" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7881418">Lohmann et al. (1994)</a> identified the same codon-661 mutation in 2 families with low penetrance. <a href="#10" class="mim-tip-reference" title="Cowell, J. K., Bia, B. <strong>A novel missense mutation in patients from a retinoblastoma pedigree showing only mild expression of the tumor phenotype.</strong> Oncogene 16: 3211-3213, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9671401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9671401</a>] [<a href="https://doi.org/10.1038/sj.onc.1201833" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9671401">Cowell and Bia (1998)</a> referred to their unpublished observations, identifying the same mutation in another family where both the 2 affected children and the unaffected father carried the arg661-to-trp (R661W) mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9671401+7881418" 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="Otterson, G. A., Modi, S., Nguyen, K., Coxon, A. B., Kaye, F. J. <strong>Temperature-sensitive RB mutations linked to incomplete penetrance of familial retinoblastoma in 12 families.</strong> Am. J. Hum. Genet. 65: 1040-1046, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10486322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10486322</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10486322[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/10.1086/302581" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10486322">Otterson et al. (1999)</a> stated that 9 families with incomplete penetrance of familial retinoblastoma and carrying a R661W mutation had been reported. Their studies of this mutation demonstrated that the mutation is temperature-sensitive. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10486322" 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">rs137853295 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853295;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=rs137853295" 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=rs137853295" 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=RCV000013963" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013963" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013963</a>
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<p>See <a href="#0019">614041.0019</a>. In a second family with incomplete penetrance of retinoblastoma (<a href="/entry/180200">180200</a>), <a href="#53" class="mim-tip-reference" title="Onadim, Z., Hogg, A., Baird, P. N., Cowell, J. K. <strong>Oncogenic point mutations in exon 20 of the RB1 gene in families showing incomplete penetrance and mild expression of the retinoblastoma phenotype.</strong> Proc. Nat. Acad. Sci. 89: 6177-6181, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1352883/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1352883</a>] [<a href="https://doi.org/10.1073/pnas.89.13.6177" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1352883">Onadim et al. (1992)</a> observed a G-to-T transversion in codon 675 that converted a glutamine (GAA) to a stop (TAA) codon. The mutation occurred near a potential cryptic splice acceptor site, raising the possibility of alternative splicing resulting in a less severely disrupted protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1352883" 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">rs587776787 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776787;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=rs587776787" 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=rs587776787" 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=RCV000013964 OR RCV002426501" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013964, RCV002426501" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013964...</a>
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<p><a href="#63" class="mim-tip-reference" title="Schubert, E. L., Strong, L. C., Hansen, M. F. <strong>A splicing mutation in RB1 in low penetrance retinoblastoma.</strong> Hum. Genet. 100: 557-563, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9341870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9341870</a>] [<a href="https://doi.org/10.1007/s004390050551" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9341870">Schubert et al. (1997)</a> found a splicing mutation in a family with incomplete penetrance and variable expressivity of retinoblastoma (<a href="/entry/180200">180200</a>) as manifested by relatively late onset, unilaterality, and occurrence of unaffected carriers. Two RB1 cDNA products were identified by PCR: the wildtype product and a mutant cDNA that lacked exon 21. Sequence analysis of genomic DNA demonstrated a G-to-A transition at the last base of exon 21. The mutant allele did not change the amino acid code; both GAG and GAA encode glu. However, the alteration reduced the match of the exon boundary splice site to the consensus. Studies indicated that the mutation severely reduced correct splicing of the mutant mRNA but did not eliminate it. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9341870" 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>.0022 RETINOBLASTOMA, TRILATERAL</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">rs121913304 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913304;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=rs121913304" 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=rs121913304" 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=RCV000013966 OR RCV000114734 OR RCV000492084" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013966, RCV000114734, RCV000492084" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013966...</a>
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<p>In a child with ectopic intracranial retinoblastoma, <a href="#54" class="mim-tip-reference" title="Onadim, Z., Woolford, A. J., Kingston, J. E., Hungerford, J. L. <strong>The RB1 gene mutation in a child with ectopic intracranial retinoblastoma.</strong> Brit. J. Cancer 76: 1405-1409, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9400934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9400934</a>] [<a href="https://doi.org/10.1038/bjc.1997.570" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9400934">Onadim et al. (1997)</a> found a nonsense mutation in exon 17 (codon 556) of the RB1 gene in homozygous (or hemizygous) state in both the retinal and the pineal tumors (<a href="/entry/180200">180200</a>). Diagnosis of bilateral retinoblastoma was made at the age of 13 months; the patient presented with the pineal tumor 32 months after the initial diagnosis of retinoblastoma. The RB1 mutation was a C-to-T transition (CGA to TGA) within a CpG dinucleotide, converting an arginine codon to a stop codon (R556X). The mutation occurred in a region of the gene that codes for part of the 'pocket' region of the Rb protein. The mutation was present heterozygously in the DNA from the constitutional cells of the patient. The mutation was absent in the blood DNA of both the father and the mother, and was shown to have occurred on the copy of the RB1 gene derived from the father. This mutation had been reported by <a href="#29" class="mim-tip-reference" title="Hogg, A., Bia, B., Onadim, Z., Cowell, J. K. <strong>Molecular mechanisms of oncogenic mutations in tumours from patients with bilateral and unilateral retinoblastoma.</strong> Proc. Nat. Acad. Sci. 90: 7351-7355, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8346255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8346255</a>] [<a href="https://doi.org/10.1073/pnas.90.15.7351" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8346255">Hogg et al. (1993)</a> in the retinal tumor from a unilateral nonhereditary case of retinoblastoma. The same mutation was identified as a germline mutation by <a href="#11" class="mim-tip-reference" title="Cowell, J. K., Smith, T., Bia, B. <strong>Frequent constitutional C to T mutations in CGA-arginine codons in the RB1 gene produce premature stop codons in patients with bilateral (hereditary) retinoblastoma.</strong> Europ. J. Hum. Genet. 2: 281-290, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7704558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7704558</a>] [<a href="https://doi.org/10.1159/000472372" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7704558">Cowell et al. (1994)</a> and <a href="#44" class="mim-tip-reference" title="Liu, Z., Song, Y., Bia, B., Cowell, J. K. <strong>Germline mutations in the RB1 gene in patients with hereditary retinoblastoma.</strong> Genes Chromosomes Cancer 14: 277-284, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8605116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8605116</a>] [<a href="https://doi.org/10.1002/gcc.2870140406" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8605116">Liu et al. (1995)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7704558+8346255+9400934+8605116" 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="0023" class="mim-anchor"></a>
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<strong>.0023 RETINOBLASTOMA</strong>
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RB1, 3-BP DEL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776788 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776788;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=rs587776788" 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=rs587776788" 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=RCV000013967 OR RCV000492635" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013967, RCV000492635" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013967...</a>
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<p><a href="#45" class="mim-tip-reference" title="Lohmann, D. R., Brandt, B., Hopping, W., Passarge, E., Horsthemke, B. <strong>Spectrum of small length germline mutations in the RB1 gene.</strong> Hum. Molec. Genet. 3: 2187-2193, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7881418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7881418</a>] [<a href="https://doi.org/10.1093/hmg/3.12.2187" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7881418">Lohmann et al. (1994)</a> described a germline del480 RB1 mutation (in-frame deletion of RB1 codon 480, resulting from a triplet nucleotide deletion) in affected members in a pedigree with retinoblastoma (<a href="/entry/180200">180200</a>) showing incomplete penetrance. <a href="#56" class="mim-tip-reference" title="Otterson, G. A., Modi, S., Nguyen, K., Coxon, A. B., Kaye, F. J. <strong>Temperature-sensitive RB mutations linked to incomplete penetrance of familial retinoblastoma in 12 families.</strong> Am. J. Hum. Genet. 65: 1040-1046, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10486322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10486322</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10486322[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/10.1086/302581" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10486322">Otterson et al. (1999)</a> demonstrated that this mutation is temperature-sensitive. The disease-eye ratio (DER) score for this family was 1.0, with 5 obligate carriers: 1 unaffected, 3 with unilateral disease, and 1 with bilateral disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7881418+10486322" 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>.0024 RETINOBLASTOMA</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">rs137853296 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853296;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=rs137853296" 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=rs137853296" 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=RCV000013968 OR RCV000492516 OR RCV002466401" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013968, RCV000492516, RCV002466401" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013968...</a>
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<p>In 2 separate previously reported families with incomplete penetrance of retinoblastoma (<a href="/entry/180200">180200</a>) and a cys712-to-arg (C712R) missense mutation in the RB1 gene, <a href="#56" class="mim-tip-reference" title="Otterson, G. A., Modi, S., Nguyen, K., Coxon, A. B., Kaye, F. J. <strong>Temperature-sensitive RB mutations linked to incomplete penetrance of familial retinoblastoma in 12 families.</strong> Am. J. Hum. Genet. 65: 1040-1046, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10486322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10486322</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10486322[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/10.1086/302581" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10486322">Otterson et al. (1999)</a> found that the mutation was temperature-sensitive. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10486322" 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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<h4>
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<strong>.0025 RETINOBLASTOMA</strong>
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RB1, IVS6, G-T, +1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776789 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776789;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=rs587776789" 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=rs587776789" 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=RCV000013969 OR RCV000484757 OR RCV000492204 OR RCV004795405" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013969, RCV000484757, RCV000492204, RCV004795405" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013969...</a>
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<p>In 2 unrelated families with incomplete penetrance of retinoblastoma (<a href="/entry/180200">180200</a>), <a href="#38" class="mim-tip-reference" title="Klutz, M., Brockmann, D., Lohmann, D. R. <strong>A parent-of-origin effect in two families with retinoblastoma is associated with a distinct splice mutation in the RB1 gene.</strong> Am. J. Hum. Genet. 71: 174-179, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12016586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12016586</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12016586[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/10.1086/341284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12016586">Klutz et al. (2002)</a> found an IVS6+1G-T splice site mutation in the RB1 gene. Analysis of RNA from white blood cells showed that this mutation causes skipping of exon 6. Although the deletion resulted in a frameshift, most carriers of the mutation did not develop retinoblastoma. The relative abundance of the resultant nonsense mRNA varied between members of the same family and was either similar to or considerably lower than the transcript level of the normal allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12016586" 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="0026" class="mim-anchor"></a>
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<h4>
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<strong>.0026 RETINOBLASTOMA</strong>
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RB1, TYR606TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137853297 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853297;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=rs137853297" 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=rs137853297" 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=RCV000013970 OR RCV002408459" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013970, RCV002408459" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013970...</a>
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<p><a href="#13" class="mim-tip-reference" title="de Jong, P. T. V. M., Mooy, C. M., Stoter, G., Eijkenboom, W. M. H., Luyten, G. P. M. <strong>Late-onset retinoblastoma in a well-functioning fellow eye.</strong> Ophthalmology 113: 1040-1044, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16631255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16631255</a>] [<a href="https://doi.org/10.1016/j.ophtha.2006.02.047" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16631255">De Jong et al. (2006)</a> described the documented growth, clinical course, and histopathology of retinoblastomas (<a href="/entry/180200">180200</a>) in an untreated and otherwise normal right eye of a 27-year-old white male with a g.153211T-A (tyr606-to-ter; W606X) mutation in the RB1 gene, whose left eye had been enucleated at age 2 years for 2 retinoblastomas. Despite extensive treatment, the right eye had to be removed due to tumor recurrences and seeding, pseudohypopyon, and elevated intraocular pressure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16631255" 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>.0027 RETINOBLASTOMA</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">rs587776790 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776790;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=rs587776790" 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=rs587776790" 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=RCV000013971" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013971" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013971</a>
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<p>In a large family with incomplete penetrance of retinoblastoma (<a href="/entry/180200">180200</a>), <a href="#62" class="mim-tip-reference" title="Sanchez-Sanchez, F., Ramirez-Castillejo, C., Weekes, D. B., Beneyto, M., Prieto, F., Najera, C., Mittnacht, S. <strong>Attenuation of disease phenotype through alternative translation initiation in low-penetrance retinoblastoma.</strong> Hum. Mutat. 28: 159-167, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16988938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16988938</a>] [<a href="https://doi.org/10.1002/humu.20394" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16988938">Sanchez-Sanchez et al. (2007)</a> identified a 23-bp duplication in exon 1 of the RB1 gene, resulting in a frameshift and premature termination in exon 2. Only 3 (30%) of 10 mutation carriers were affected by disease. RT-PCR analysis showed that the mutation did not induce nonsense-mediated decay. Transcript expression in cultured cells showed that downstream alternative in-frame translation sites involving met113 and possibly met223 were used to generate N-terminal truncated RB1 products known and suspected to exhibit tumor suppressor activity. The findings suggested that modulation of disease penetrance in this family was achieved by internal translation initiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16988938" 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">rs587776791 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776791;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=rs587776791" 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=rs587776791" 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=RCV000013972 OR RCV003321482" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013972, RCV003321482" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013972...</a>
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<p>In 2 brothers with retinoblastoma (<a href="/entry/180200">180200</a>) diagnosed at age 2 years, <a href="#15" class="mim-tip-reference" title="Dehainault, C., Michaux, D., Pages-Berhouet, S., Caux-Moncoutier, V., Doz, F., Desjardins, L., Couturier, J., Parent, P., Stoppa-Lyonnet, D., Gauthier-Villars, M., Houdayer, C. <strong>A deep intronic mutation in the RB1 gene leads to intronic sequence exonisation.</strong> Europ. J. Hum. Genet. 15: 473-477, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17299438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17299438</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201787" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17299438">Dehainault et al. (2007)</a> identified a -1398A-G transition in intron 23 of the RB1 gene (IVS23AS-1398A-G), resulting in a 103-bp insertion between exons 23 and 24. In silico analysis demonstrated the creation of a cryptic splice site leading to an intronic sequence exonization. The unaffected father also carried the mutation, likely in a mosaic state. The mutation was not identified by point mutation or large rearrangement screening and was only detected by complete transcript analysis using RNA extracted from the patients' lymphoblastoid cells treated with puromycin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17299438" 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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<a id="Bookstein1988" class="mim-anchor"></a>
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Bookstein, R., Lee, E. Y.-H. P., To, H., Young, L.-J., Sery, T. W., Hayes, R. C., Friedmann, T., Lee, W.-H.
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<strong>Human retinoblastoma susceptibility gene: genomic organization and analysis of heterozygous intragenic deletion mutants.</strong>
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Proc. Nat. Acad. Sci. 85: 2210-2214, 1988.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2895471/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2895471</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2895471" 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/10.1073/pnas.85.7.2210" target="_blank">Full Text</a>]
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Brown, V. D., Gallie, B. L.
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<strong>The B-domain lysine patch of pRB is required for binding to large T antigen and release of E2F by phosphorylation .</strong>
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Molec. Cell. Biol. 22: 1390-1401, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11839806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11839806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11839806[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=11839806" 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/10.1128/MCB.22.5.1390-1401.2002" target="_blank">Full Text</a>]
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Buchkovich, K., Duffy, L. A., Harlow, E.
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<strong>The retinoblastoma protein is phosphorylated during specific phases of the cell cycle.</strong>
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Cell 58: 1097-1105, 1989.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2673543/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2673543</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2673543" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0092-8674(89)90508-4" target="_blank">Full Text</a>]
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<a id="Calo2010" class="mim-anchor"></a>
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Calo, E., Quintero-Estades, J. A., Danielian, P. S., Nedelcu, S., Berman, S. D., Lees, J. A.
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<strong>Rb regulates fate choice and lineage commitment in vivo.</strong>
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Nature 466: 1110-1114, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20686481/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20686481</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20686481[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=20686481" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature09264" target="_blank">Full Text</a>]
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Carreira, S., Goodall, J., Aksan, I., La Rocca, S. A., Galibert, M.-D., Denat, L., Larue, L., Goding, C. R.
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<strong>Mitf cooperates with Rb1 and activates p21(Cip1) expression to regulate cell cycle progression.</strong>
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Nature 433: 764-769, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15716956/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15716956</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15716956" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature03269" target="_blank">Full Text</a>]
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Cavenee, W. K.
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Trends Genet. 2: 299-300, 1986.
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Chano, T., Ikegawa, S., Kontani, K., Okabe, H., Baldini, N., Saeki, Y.
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<strong>Identification of RB1CC1, a novel human gene that can induce RB1 in various human cells.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11850849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11850849</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11850849" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/sj.onc.1205178" target="_blank">Full Text</a>]
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Chen, P.-L., Scully, P., Shew, J.-Y., Wang, J. Y. J., Lee, W.-H.
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<strong>Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentiation.</strong>
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Cell 58: 1193-1198, 1989.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2673546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2673546</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2673546" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0092-8674(89)90517-5" target="_blank">Full Text</a>]
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Cornwell, J. A., Crncec, A., Afifi, M. M., Tang, K., Amin, R., Cappell, S. D.
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<strong>Loss of CDK4/6 activity in S/G2 phase leads to cell cycle reversal.</strong>
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Nature 619: 363-370, 2023. Note: Erratum: Nature 630: E14, 2024.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37407814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37407814</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37407814[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=37407814" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/s41586-023-06274-3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1128/MCB.26.4.1170-1182.2006" target="_blank">Full Text</a>]
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<a id="Xu2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Xu, X. L., Singh, H. P., Wang, L., Qi, D.-L., Poulos, B. K., Abramson, D. H., Jhanwar, S. C., Cobrinik, D.
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<strong>Rb suppresses human cone-precursor-derived retinoblastoma tumours.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25252974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25252974</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25252974[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=25252974" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature13813" target="_blank">Full Text</a>]
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<div class="">
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<p class="mim-text-font">
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Yandell, D. W., Campbell, T. A., Dayton, S. H., Petersen, R., Walton, D., Little, J. B., McConkie-Rosell, A., Buckley, E., Dryja, T.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2594029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2594029</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2594029" 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/10.1056/NEJM198912213212501" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="81" class="mim-anchor"></a>
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<a id="Yokota1988" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yokota, J., Akiyama, T., Fung, Y.-K. T., Benedict, W. F., Namba, Y., Hanaoka, M., Wada, M., Terasaki, T., Shimosato, Y., Sugimura, T., Terada, M.
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<strong>Altered expression of the retinoblastoma (RB) gene in small-cell carcinoma of the lung.</strong>
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Oncogene 3: 471-475, 1988.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2856251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2856251</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2856251" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="82" class="mim-anchor"></a>
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<a id="Zatulovskiy2020" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zatulovskiy, E., Zhang, S., Berenson, D. F., Topacio, B. R., Skotheim, J. M.
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<strong>Cell growth dilutes the cell cycle inhibitor Rb to trigger cell division.</strong>
|
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Science 369: 466-471, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32703881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32703881</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32703881[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=32703881" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.aaz6213" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="83" class="mim-anchor"></a>
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<a id="Zhang1999" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
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Zhang, H. S., Postigo, A. A., Dean, D. C.
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<strong>Active transcriptional repression by the Rb-E2F complex mediates G1 arrest triggered by p16(INK4a), TGF-beta, and contact inhibition.</strong>
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Cell 97: 53-61, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10199402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10199402</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10199402" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(00)80714-x" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="84" class="mim-anchor"></a>
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<a id="Zhang2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, J., Benavente, C. A., McEvoy, J., Flores-Otero, J., Ding, L., Chen, X., Ulyanov, A., Wu, G., Wilson, M., Wang, J., Brennan, R., Rusch, M., and 24 others.
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<strong>A novel retinoblastoma therapy from genomic and epigenetic analyses.</strong>
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Nature 481: 329-334, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22237022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22237022</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22237022[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=22237022" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature10733" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="85" class="mim-anchor"></a>
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<a id="Zhang2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, J., Gray, J., Wu, L., Leone, G., Rowan, S., Cepko, C. L., Zhu, X., Craft, C. M., Dyer, M. A.
|
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<strong>Rb regulates proliferation and rod photoreceptor development in the mouse retina.</strong>
|
|
Nature Genet. 36: 351-360, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14991054/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14991054</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14991054" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng1318" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
|
|
<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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Bao Lige - updated : 02/08/2024
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</span>
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</div>
|
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</div>
|
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
|
|
Ada Hamosh - updated : 10/29/2020<br>Ada Hamosh - updated : 12/19/2019<br>Ada Hamosh - updated : 01/29/2018<br>Matthew B. Gross - updated : 04/20/2016<br>Ada Hamosh - updated : 11/4/2014<br>Ada Hamosh - updated : 2/8/2012
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
|
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
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<span class="text-nowrap mim-text-font">
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Creation Date:
|
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
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Carol A. Bocchini : 6/14/2011
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
|
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
|
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 07/19/2024
|
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</span>
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</div>
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</div>
|
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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|
mgross : 02/08/2024<br>mgross : 12/08/2020<br>mgross : 10/29/2020<br>alopez : 12/19/2019<br>carol : 11/25/2019<br>carol : 11/22/2019<br>carol : 11/21/2019<br>carol : 09/05/2019<br>carol : 01/30/2018<br>alopez : 01/29/2018<br>mgross : 04/20/2016<br>alopez : 11/4/2014<br>terry : 3/14/2013<br>alopez : 2/13/2012<br>terry : 2/8/2012<br>alopez : 9/23/2011<br>mgross : 6/21/2011<br>terry : 6/17/2011<br>carol : 6/17/2011<br>carol : 6/17/2011
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
|
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<span class="mim-font">
|
|
<strong>*</strong> 614041
|
|
</span>
|
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</h3>
|
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</div>
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|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
RB TRANSCRIPTIONAL COREPRESSOR 1; RB1
|
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|
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</span>
|
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</h3>
|
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</div>
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<div>
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<br />
|
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</div>
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<div>
|
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<div >
|
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<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
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</span>
|
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</p>
|
|
</div>
|
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
p105-Rb
|
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</span>
|
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</h4>
|
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</div>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: RB1</em></strong>
|
|
</span>
|
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</p>
|
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</div>
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<div>
|
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<p>
|
|
<span class="mim-text-font">
|
|
|
|
<strong>SNOMEDCT:</strong> 19906005, 370967009;
|
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</span>
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</p>
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</div>
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<div>
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<br />
|
|
</div>
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|
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<div>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: 13q14.2
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 13:48,303,751-48,481,890 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="5">
|
|
<span class="mim-font">
|
|
13q14.2
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Bladder cancer, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
109800
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Osteosarcoma, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
259500
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Retinoblastoma
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
180200
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant; Somatic mutation
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Retinoblastoma, trilateral
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
180200
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant; Somatic mutation
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
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Small cell cancer of the lung, somatic
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182280
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<strong>TEXT</strong>
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<p>Dryja et al. (1984) cloned DNA fragments from chromosome 13. Three of these identified RFLPs from region 13q12-q22, which contains the retinoblastoma (180200) 'locus.'</p><p>Friend et al. (1986) isolated a cDNA that detects a chromosomal segment having the properties of the gene at the retinoblastoma locus. The gene was found to be expressed in many tumor types, but no RNA transcript was found in retinoblastomas or osteosarcomas. The locus spanned at least 70 kb of DNA. Friend et al. (1986) started with a 1.5 kb DNA sequence which could detect deletions involving 13q14 in 3 of 37 retinoblastomas. They then used chromosome walking techniques to isolate and map 30 kb of surrounding genomic DNA. One of the single-copy fragments recognized a DNA sequence in the mouse genome and also in human chromosome 13. The conservation of this DNA sequence between mouse and humans suggested that the cloned fragment contained a coding exon of a gene. Therefore, they tested the ability of this fragment to hybridize to RNA derived from retinoblastoma cells and from human retinal cells. They found that indeed it recognized a 4.7-kb RNA transcript in the retinal cell line but that this transcript was not detectable in 4 retinoblastomas. </p><p>As outlined by Cavenee (1986), when the cDNA described by Friend et al. (1986) was used as a probe to screen RNA samples from different tumor types, it was shown to hybridize to all of those tested except retinoblastomas and retinoblastoma-associated osteosarcomas. Furthermore, use of this cDNA to analyze the genomic structure of its homologous locus in 50 retinoblastomas or associated osteosarcomas showed that about 30% had somatically altered genomic loci. These alterations took the form of fragments of altered mobility (suggesting gene rearrangements), underrepresented fragments (suggesting heterozygous deletions), and missing fragments (suggesting homozygous deletions). Since one of the homozygous deletions was entirely contained within the genomic locus homologous to the cDNA probe, it was suggested that this expressed gene was indeed the RB1 gene. </p><p>Dryja et al. (1986) isolated a cDNA fragment derived from human retinal mRNA that detected a locus within 13q14 that is often deleted in retinoblastoma.</p><p>Lee et al. (1987) prepared a rabbit antiserum against the RB protein studied by Horsthemke et al. (1987) and showed that it was present in all cell lines expressing normal RB mRNA but was not detected in 5 retinoblastoma cell lines. The RB protein can be metabolically labeled with (32)P-phosphoric acid, indicating that it is a phosphoprotein. Biochemical fractionation and immunofluorescence studies demonstrated that most of the protein is located in the nucleus. Furthermore, the protein was retained by and could be eluted from DNA-cellulose columns, suggesting a DNA binding activity. </p><p>A gene encoding a messenger RNA of 4.6 kb, located in the proximity of esterase D (133280), was identified by Lee et al. (1987) as the retinoblastoma susceptibility gene on the basis of chromosomal location, homozygous deletion, and tumor-specific alterations in expression. Transcription of the gene was abnormal in all of 6 retinoblastomas examined: in 2, mRNA was not detectable, whereas 4 others expressed variable quantities of the mRNA with decreased molecular size of about 4.0 kb. In contrast, full-length RB mRNA was present in human fetal retina and placenta, and in other tumors such as neuroblastoma and medulloblastoma. The sequence of cDNA clones indicated a hypothetical protein of 816 amino acids. </p><p>Whyte et al. (1988) demonstrated that a 105,000-Da cellular protein, which is one of the cellular targets implicated in the process of transformation by the adenovirus E1A proteins, is in fact the product of the RB1 gene. This interaction with the formation of a stable protein/protein complex was the first demonstration of a physical link between an oncogene and an antioncogene. A similar case can be made for numerous other disorders, many of which are more common. </p><p>Toguchida et al. (1993) reported the complete genomic sequence of the RB1 gene, which was contained in a 180,388-bp contig. The gene produces a 4.7-kb transcript that encodes a nuclear phosphoprotein consisting of 928 amino acids. </p>
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<p>Hong et al. (1989) demonstrated that the RB transcript is encoded in 27 exons dispersed over about 200 kb of genomic DNA. The length of individual exons ranges from 31 to 1,889 bp. The largest intron spans more than 60 kb and the smallest one has only 80 bp. Deletion of exons 13-17 is frequently observed in various types of tumors, including retinoblastoma, breast cancer, and osteosarcoma, and the presence of a potential 'hotspot' for recombination in the region was predicted. A putative 'leucine-zipper' motif is exclusively encoded by exon 20. Transcription of RB is initiated at multiple positions and the sequences surrounding the initiation sites have a high G+C content. Several features of the RB promoter are reminiscent of those associated with many so-called housekeeping genes, consistent with the ubiquitous expression of the RB gene. </p>
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<p>Stone et al. (1989) mapped the mouse homolog of the human retinoblastoma gene, symbolized Rb1, to chromosome 14 by analysis of somatic cell hybrids. In recombinant inbred strains, the findings suggested close linkage of Rb1 and Es10, which appears to be the mouse homolog of ESD (133280). By in situ hybridization, Ono and Yoshida (1993) assigned the RB1 gene to mouse 14D3 and the rat homolog to 15q12. A unique sequence human RB1 cosmid DNA probe was used by Verma et al. (1996) to localize the RB1 homolog in chimpanzee, gorilla, and orangutan to chromosome 14 by fluorescence in situ hybridization. </p><p>Analysis of the RB1 gene sequence by Toguchida et al. (1993) indicated a high ratio of (A+T)/(G+C) and a high density of Line-1 (L1) repeat sequences, suggesting that the gene maps to G-bands 13q14.12 or 13q14.2. </p>
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<p>DeCaprio et al. (1989), Buchkovich et al. (1989), and Chen et al. (1989) demonstrated that the RB1 gene product has the properties of a cell cycle regulatory element and that its function is modulated by a phosphorylation/dephosphorylation mechanism during cell proliferation and differentiation. In G0/G1 cells, virtually all the RB protein is unphosphorylated, whereas during S and G2 phases, it is largely, if not exclusively, phosphorylated. </p><p>Shiio et al. (1992) found evidence that wildtype p53 suppresses transcription of the RB gene. From deletion and mutagenesis experiments, a cis-acting element (GGAAGTGA) susceptible to regulation by p53 was mapped within the RB promoter. </p><p>Mancini et al. (1994) demonstrated by immunoblotting and immunolabeling that a significant portion of hypophosphorylated Rb associates with the nuclear matrix during the early G1 phase. They suggested that Rb interactions with a nuclear matrix may be important for its ability to regulate cell cycle progression. Mutant Rb in tumor cells did not associate with the matrix, whereas Rb-reconstituted cells contained abundant matrix-bound Rb. </p><p>Weinberg (1995) reviewed the role of the RB protein in the control of the cell cycle. </p><p>Fearon (1997) provided a schematic representation of the cellular localization and presumed functions of the proteins encoded by inherited cancer genes. </p><p>Luo et al. (1998) demonstrated that Rb can repress transcription of endogenous cell cycle genes containing E2F sites through recruitment of histone deacetylase, which deacetylates histones on the promoter, thereby promoting formation of nucleosomes that inhibit transcription. </p><p>RB inhibits progression from G1 to S phase of the cell cycle and associates with a number of cellular proteins. Zhang et al. (1999) presented evidence that RB must normally interact with the E2F family of transcription factors to arrest cells in G1, and that this arrest results from active transcriptional repression by the RB-E2F complex, not from inactivation of E2F. Thus, a major role of E2F in cell cycle regulation is assembly of this repressor complex. Zhang et al. (1999) demonstrated that active repression by the RB-E2F complex mediates the G1 arrest triggered by transforming growth factor-beta (TGFB; 190180), p16(INK4A) (CDKN2A; 600160), and contact inhibition. </p><p>Harbour et al. (1999) presented evidence that phosphorylation of the C-terminal region of RB by CDK4 (123829)/CDK6 (603368) initiates successive intramolecular interactions between the C-terminal region and the central pocket. The initial interaction displaces histone deacetylase from the pocket, blocking active transcriptional repression by RB. This facilitates a second interaction that leads to phosphorylation of the pocket by CDK2 (116953) and disruption of pocket structure. These intramolecular interactions provide a molecular basis for sequential phosphorylation of RB by CDK4/CDK6 and CDK2. CDK4/CDK6 is activated early in G1, blocking active repression by RB. However, it is not until near the end of G1, when cyclin E (see 123837) is expressed and CDK2 is activated, that RB is prevented from binding and inactivating E2F. </p><p>Hsieh et al. (1999) showed that the binding of RB to MDM2 (164785) is essential for RB to overcome both the antiapoptotic function of MDM2 and the MDM2-dependent degradation of p53. Since RB specifically rescues the apoptotic function but not the transcriptional activity of p53 from negative regulation by MDM2, transactivation by wildtype p53 is not required for the apoptotic function of p53. These data demonstrated a role of RB in regulating the apoptotic function of p53. </p><p>Hanahan and Weinberg (2000) referred to deregulation of the retinoblastoma protein pathway as a 'hallmark of cancer.' In the absence of other genetic alterations, deregulation results in lack of differentiation, hyperproliferation, and apoptosis. The RB protein acts as a transcriptional repressor by targeting the E2F transcription factors (e.g., 189971), whose functions are required for entry into S phase. Increased E2F activity can induce S phase in quiescent cells; this is a central element of most models for the development of cancer. Lomazzi et al. (2002) showed that increased E2F1 activity can result in S phase entry in diploid fibroblasts only when the p53 (191170)-mediated G1 checkpoint is suppressed. They showed that E2F1 can induce S phase in primary mouse fibroblasts lacking Rb protein. These results indicated that in addition to acting as an E2F-dependent transcriptional repressor, RB protein is also required for the cells to retain the G1 checkpoint in response to unprogrammed proliferative signals. </p><p>Pennaneach et al. (2001) showed that the LxCxE-binding site in RB1 mediates both cell survival and cell cycle arrest after DNA damage. Replication factor C (RFC) complex plays an important role in DNA replication. Pennaneach et al. (2001) described a function of the large subunit of RFC, RFC1 (102579), in promoting cell survival after DNA damage. RFC1 contains an LxCxE motif, and mutation of this motif abolished the protective effect of RFC1. The inability of wildtype RFC1 to promote cell survival in RB1-null cells was rescued by RB1 but not by RB1 mutants defective in binding LxCxE proteins. RFC thus enhances cell survival after DNA damage in an RB1-dependent manner. </p><p>Nielsen et al. (2001) demonstrated that SUV39H1 (300254) and HP1 (604478) are both involved in the repressive functions of the retinoblastoma protein. Rb associates with SUV39H1 and HP1 in vivo by means of its pocket domain. SUV39H1 cooperates with Rb to repress the cyclin E (123837) promoter, and in fibroblasts that are disrupted for SUV39H1, the activity of the cyclin E and cyclin A2 (123835) genes are specifically elevated. Chromatin immunoprecipitation showed that Rb is necessary to direct methylation of histone H3, and is necessary for binding of HP1 to the cyclin E promoter. Nielsen et al. (2001) concluded that the SUV39H1-HP1 complex is not only involved in heterochromatic silencing but also has a role in repression of euchromatic genes by Rb and perhaps other corepressor proteins. </p><p>Dahiya et al. (2001) found that association between RB and Polycomb group (PcG; see 300227) proteins forms a repressor complex that blocks entry of cells into mitosis. Also, they provided evidence that RB colocalizes with nuclear PcG complexes and is important for association of PcG complexes with nuclear targets. The RB-PcG complex may provide a means to link cell cycle arrest to differentiation events leading to embryonic pattern formation. </p><p>The incidence of osteosarcoma is increased 500-fold in patients who inherit mutations in the RB gene. To understand why the RB protein is specifically targeted in osteosarcoma, Thomas et al. (2001) studied its function in osteogenesis. Loss of RB but not p107 (116957) or p130 (180203) blocked late osteoblast differentiation. RB physically interacted with the osteoblast transcription factor, CBFA1 (600211), and associated with osteoblast-specific promoters in vivo in a CBFA1-dependent fashion. Association of RB with CBFA1 and promoter sequences resulted in synergistic transactivation of an osteoblast-specific reporter. This transactivation function was lost in tumor-derived RB mutants, underscoring a potential role in tumor suppression. Thus, RB functions as a direct transcriptional coactivator promoting osteoblast differentiation, which may contribute to the targeting of RB in osteosarcoma. </p><p>By yeast 2-hybrid analysis using a human fibroblast cDNA library and protein pull-down assays with human EJ bladder cancer cells and Saos2 osteosarcoma cells, Leung et al. (2001) showed that MRG15 (MORF4L1; 607303) interacted with PAM14 (MRFAP1; 616905) and RB. Deletion analysis showed that the helix-loop-helix and leucine zipper regions of MRG15 were important for interaction with both PAM14 and RB. Immunoprecipitation analysis of EJ cells and human fibroblasts revealed that MRG15, PAM14, and RB were present in a multiprotein complex. Luciferase assays showed that MRG15 blocked RB-induced repression of the BMYB (MYBL2; 601415) promoter, leading to BMYB promoter activation. Leung et al. (2001) concluded that MRG15 regulates transcription through interactions with a complex containing RB and PAM14. </p><p>Using immunoprecipitation and immunoblot analyses, Tominaga et al. (2004) showed that Mrg15 interacted with Pam14 and Rb in mouse cells, similar to findings in human cells. </p><p>Fajas et al. (2002) found that Pparg (601487) promoted adipocyte differentiation more efficiently in Rb-deficient mouse embryonic fibroblasts than in Rb-expressing controls. Pparg and Rb coimmunoprecipitated, and the Pparg-Rb complex also contained histone deacetylase-3 (HDAC3; 605166). Rb recruited Hdac3 to the Pparg-Rb complex, and recruitment attenuated Pparg-mediated gene expression and adipocyte differentiation. Dissociation of the Pparg-Rb-Hdac3 complex by Rb phosphorylation or inhibition of Hdac activity stimulated adipocyte differentiation. </p><p>Chano et al. (2002) identified and cloned an RB1-inducible coiled-coil protein (RB1CC1; 606837) by differential display between a multidrug resistant osteosarcoma cell line and the sensitive parental cell line. By semiquantitative RT-PCR of a panel of cancer cell lines, they observed a close correlation between expression of RB1 and expression of RB1CC1. In addition, they found that exogenous expression of RB1CC1 in 2 leukemia cell lines produced a marked increase in RB1 expression. The induction was found to be due to the activation of the RB1 promoter by RB1CC1. </p><p>Garcia-Cao et al. (2002) reported a connection between members of the retinoblastoma family of proteins, RB1, RBL1 (116957), and RBL2 (180203), and the mechanisms that regulate telomere length. In particular, mouse embryonic fibroblasts doubly deficient in Rbl1 and Rbl2 or triply deficient in all 3 genes had markedly elongated telomeres compared with those of wildtype or Rb1-deficient cells. This deregulation of telomere length was not associated with increased telomerase (see 187270) activity. The abnormal elongated telomeres in doubly or triply deficient cells retained their end-capping function, as shown by the normal frequency of chromosomal fusions. These findings demonstrated a connection between the RB1 family and the control of telomere length in mammalian cells. </p><p>Brown and Gallie (2002) stated that interaction of mouse Rb with E2f on DNA is regulated by accumulation of phosphate groups in the C-terminal domain of Rb. By mutation analysis, they identified a 6-lysine basic patch in the Rb B domain that was necessary for release of Rb from E2f on DNA and for interaction of Rb with SV40 T antigen. Brown and Gallie (2002) suggested that release of E2F from Rb involves a conformational change whereby the C-terminal domain interacts with the B domain following phosphorylation by cyclin E. </p><p>Cellular senescence is a stable form of cell cycle arrest that limits proliferation of damaged cells and may act as a natural barrier to cancer progression. Narita et al. (2003) described a distinct heterochromatic structure that accumulates in senescent human fibroblasts, designated senescence-associated heterochromatic foci (SAHF). They found that SAHF formation coincides with recruitment of heterochromatin proteins and the RB1 protein to E2F-responsive promoters and is associated with the stable repression of E2F target genes. Both SAHF formation and the silencing of E2F target genes depended on the integrity of the RB pathway and did not occur in reversibly arrested cells. </p><p>The RB gene regulates proliferation, cell fate specification, and differentiation in the developing central nervous system. In the postnatal developing mouse retina, Zhang et al. (2004) found that Rb is expressed in proliferating retinal progenitor cells and differentiating rod photoreceptors. In retinal cell cultures from Rb-null mice and retinal cells from transgenic mice with targeted inactivation of the Rb gene, retinal progenitor cells continued to divide and rods did not mature, suggesting that Rb plays a role in cell proliferation and rod photoreceptor development. </p><p>Iavarone et al. (2004) showed that Rb-deficient embryos carry profound abnormalities of fetal liver macrophages that prevent physical interactions with erythroblasts. In contrast, wildtype macrophages bind Rb-deficient erythroblasts and lead to terminal differentiation and enucleation. Loss of Id2 (600386), a helix-loop-helix protein that mediates the lethality of Rb-deficient embryos, rescues the defects of Rb-deficient fetal liver macrophages. Rb promotes differentiation of macrophages by opposing the inhibitory functions of Id2 on the transcription factor PU.1 (165170), a master regulator of macrophage differentiation. Thus, Rb has a cell-autonomous function in fetal liver macrophages, and restrains Id2 in these cells to implement definitive erythropoiesis. </p><p>Sekimata and Homma (2004) developed a mouse myoblast cell line constitutively overexpressing Mizf (607099). When switched to differentiation medium, these cells showed decreased expression of Rb and several differentiation markers, and consequently could not differentiate into multinucleated myotubes. Sekimata and Homma (2004) concluded that repression of RB by MIZF is a critical determinant of myogenic differentiation. </p><p>Carreira et al. (2005) showed that cooperation between MITF (156845) and RB1 potentiates the ability of MITF to activate transcription. Carreira et al. (2005) suggested that MITF-mediated activation of p21(Cip1) (CDKN1A; 116899) expression and consequent hypophosphorylation of RB1 contributes to cell cycle exit and activation of the differentiation program. </p><p>Caenorhabditis elegans homologs of the Rb tumor suppressor complex specify cell lineage during development. Wang et al. (2005) showed that mutations in Rb pathway components enhanced RNA interference and caused somatic cells to express genes and elaborate perinuclear structures normally limited to germline-specific P granules. Furthermore, particular gene inactivations that disrupted RNA interference (RNAi) reversed the cell lineage transformations of Rb pathway mutants. Wang et al. (2005) concluded that mutations in Rb pathway components cause cells to revert to patterns of gene expression normally restricted to germ cells in C. elegans. </p><p>By profiling gene expression in developing mouse vestibular organs, Sage et al. (2005) identified the Rb protein as a candidate regulator of cell cycle exit in hair cells. Differentiated and functional mouse hair cells with a targeted deletion of Rb1 undergo mitosis, divide, and cycle, yet continue to become highly differentiated and functional. Moreover, acute loss of Rb1 in postnatal hair cells caused cell cycle reentry. </p><p>Using a yeast 2-hybrid screen to identify proteins that affect RB-mediated gene activation, Krutzfeldt et al. (2005) found that RFP (TRIM27; 602165) strongly reduced the effect of RB on glucocorticoid receptor (GCCR; 138040)-mediated transcription, but it did not prevent the ability of RB to inhibit E2F-mediated transcription. Mutation analysis showed that RFP interacted with the large pocket of RB in a manner distinct from that of E2F. Krutzfeldt et al. (2005) proposed that RFP expression may neutralize the RB-mediated differentiation response while leaving in place E2F-dependent cell cycle regulation and apoptosis protection. </p><p>Laurie et al. (2006) showed that the tumor surveillance pathway mediated by ARF (see 600160), MDM2 (164785), MDMX (602704), and p53 (191170) is activated after loss of RB1 during retinogenesis. RB1-deficient retinoblasts undergo p53-mediated apoptosis and exit the cell cycle. Subsequently, amplification of the MDMX gene and increased expression of MDMX protein are strongly selected for during tumor progression as a mechanism to suppress the p53 response in RB1-deficient retinal cells. Laurie et al. (2006) concluded that their data provided evidence that the p53 pathway is inactivated in retinoblastoma and that this cancer does not originate from intrinsically death-resistant cells as previously thought. In addition, Laurie et al. (2006) suggested that their data supported the idea that MDMX is a specific chemotherapeutic target for treating retinoblastoma. </p><p>Williams et al. (2006) found that mouse fibroblasts lacking Rb were less susceptible to an oncogenic HRAS (190020) allele than wildtype cells. Depletion of RB from HRAS-transformed mouse cells or human tumor cells harboring HRAS pathway mutations inhibited their proliferation and anchorage-independent growth. In contrast to Rb -/- mouse fibroblasts, p107 -/- and p130 -/- fibroblasts were more susceptible to HRAS-mediated transformation than wildtype cells. Moreover, loss of RB in human tumor cells harboring an HRAS mutation resulted in increased expression of p107, and overexpression of p107, but not RB, strongly inhibited proliferation of these tumor cells. Williams et al. (2006) concluded that RB and p107 have distinct roles in HRAS-mediated transformation and that p107 has a role as a tumor suppressor in the context of activated HRAS. </p><p>Morris et al. (2008) demonstrated that E2F1 (189971) is a potent and specific inhibitor of beta-catenin (116806)/T cell factor (TCF)-dependent transcription and that this function contributes to E2F1-induced apoptosis. E2F1 deregulation suppresses beta-catenin activity in an adenomatous polyposis coli (APC; 611731)/glycogen synthase kinase-3 (GSK3; see 606784)-independent manner, reducing the expression of key beta-catenin targets including c-MYC. This interaction explains why colorectal tumors, which depend on beta-catenin transcription for their abnormal proliferation, keep RB1 intact. Remarkably, E2F1 activity is also repressed by cyclin-dependent kinase-8 (CDK8; 603184), a colorectal oncoprotein. Elevated levels of CDK8 protect beta-catenin/TCF-dependent transcription from inhibition by E2F1. Morris et al. (2008) concluded that thus, by retaining RB1 and amplifying CDK8, colorectal tumor cells select conditions that collectively suppress E2F1 and enhance the activity of beta-catenin. </p><p>Hume et al. (2008) showed that cytomegalovirus UL97 protein, like human cyclin-dependent kinases (see CDK2, 116953), phosphorylates RB, but does so in a cyclin-independent manner and is poorly inhibited by p21 (CDKN1A; 116899). Hume et al. (2008) concluded that UL97 is functionally orthologous to human CDK in phosphorylating RB but is immune from normal CDK control mechanisms. </p><p>Dgcr8 (609030)-knockout mouse embryonic stem (ES) cells lack microRNAs (miRNAs), proliferate slowly, and accumulate in G1 phase of the cell cycle. By screening mouse miRNAs for those that could rescue the growth defect in Dgcr8-knockout mouse ES cells, Wang et al. (2008) identified a group of related ES cell-specific miRNAs, including several members of the miR290 cluster. Target sites for these miRNAs were identified in the 3-prime UTRs of several inhibitors of the cyclin E-CDK2 pathway, including Cdkn1a, Rb1, Rbl1, Rbl2, and Lats2 (604861). Quantitative RT-PCR confirmed increased expression of these genes in Dgcr8-knockout mouse ES cells. </p><p>Wang et al. (2010) found that inactivation of Skp2 (601436), which is a target of Rb1, completely prevented spontaneous tumorigenesis in pituitaries of Rb1 +/- mice. Skp2 inactivation did not inhibit aberrant proliferation in Rb1-deleted melanotrophs but induced their apoptotic death. Elimination of p27 (600778) phosphorylation reproduced the effects of Skp2 knockout. Wang et al. (2010) concluded that downregulation of RB1 is tumorigenic due to unregulated SKP2-mediated ubiquitination of phosphorylated p27, followed by p27 degradation and cell cycle progression. </p><p>Depending on the differentiation factor and cellular context, the Rb protein can either suppress or promote the transcriptional activity of several master differentiation inducers. For example, Rb protein binds to RUNX2 (600211) and potentiates its ability to promote osteogenic differentiation in vitro. In contrast, Rb protein acts with E2F to suppress PPARG (601487), the master activator of adipogenesis. Because osteoblasts and adipocytes can both arise from mesenchymal stem cells, these observations suggest that Rb protein might play a role in the choice between these 2 fates. Calo et al. (2010) used mouse models to address this hypothesis in mesenchymal tissue development and tumorigenesis and showed that Rb status plays a key role in establishing fate choice between bone and brown adipose tissue in vivo. </p><p>Based on genomewide methylation analysis of a patient with multiple imprinting defects, Kanber et al. (2009) identified a differentially methylated CpG island in intron 2 of the RB1 gene. The CpG island is part of a 5-prime truncated, processed pseudogene derived from the KIAA0649 gene (614056) on chromosome 9 and corresponds to 2 small CpG islands in the open reading frame of the ancestral gene. It is methylated on the maternal chromosome 13 and acts as a weak promoter for an alternative RB1 transcript on the paternal chromosome 13. In 4 other KIAA0649 pseudogene copies, which are located on chromosome 22, the 2 CpG islands have deteriorated and the CpG dinucleotides are fully methylated. By analyzing allelic RB1 transcript levels in blood cells, as well as in hypermethylated and 5-aza-2-prime-deoxycytidine-treated lymphoblastoid cells, Kanber et al. (2009) found that differential methylation of the CpG island (CpG 85) skews RB1 gene expression in favor of the maternal allele. Thus, Kanber et al. (2009) concluded that RB1 is imprinted in the same direction as CDKN1C (600856), which operates upstream of RB1. The imprinting of 2 components of the same pathway indicates that there has been strong evolutionary selection for maternal inhibition of cell proliferation. </p><p>Xu et al. (2014) showed that postmitotic human cone precursors are uniquely sensitive to RB depletion. RB knockdown induced cone precursor proliferation in prospectively isolated populations and in intact retina. Proliferation followed the induction of E2F-regulated genes, and depended on factors having strong expression in maturing cone precursors and crucial roles in retinoblastoma cell proliferation, including MYCN (164840) and MDM2 (164785). Proliferation of RB-depleted cones and retinoblastoma cells also depended on the RB-related protein p107 (RBL1; 116957), SKP2 (601436), and a p27 (CDKN1B; 600778) downregulation associated with cone precursor maturation. Moreover, RB-depleted cone precursors formed tumors in orthotopic xenografts with histologic features and protein expression typical of human retinoblastoma. Xu et al. (2014) concluded that these findings provide a compelling molecular rationale for a cone precursor origin of retinoblastoma. </p><p>In mice, Walter et al. (2019) modeled RB loss during lung adenocarcinoma progression and pathway reactivation in established oncogenic KRAS (190070)-driven tumors. They showed that RB loss enables cancer cells to bypass 2 distinct barriers during tumor progression. First, RB loss abrogates the requirement for amplification of the mitogen-activated protein kinase (MAPK; see 176948) signal during malignant progression. Walter et al. (2019) identified CDK2 (116953)-dependent phosphorylation of RB as an effector of MAPK signaling and critical mediator of resistance to inhibition of CDK4 (123829) and CDK6 (603368). Second, RB inactivation deregulates the expression of cell-state-determining factors, facilitates lineage infidelity, and accelerates the acquisition of metastatic competency. By contrast, reactivation of RB reprograms advanced tumors towards a less metastatic cell state, but is nevertheless unable to halt cancer cell proliferation and tumor growth due to adaptive rewiring of MAPK pathway signaling, which restores a CDK-dependent suppression of RB. </p><p>Zatulovskiy et al. (2020) showed that cell growth during G1 phase of the cell division cycle diluted RB to trigger division in human cells. RB overexpression increased cell size and G1 duration, whereas RB deletion decreased cell size and removed the inverse correlation between cell size at birth and duration of G1 phase. Zatulovskiy et al. (2020) concluded that RB dilution through cell growth in G1 provides a molecular mechanism that promotes cell size homeostasis. </p><p>The restriction (R) point marks the point in the cell cycle when cells become independent of mitogen signaling and CDK2 activity becomes self-sustaining through a feedback loop between cyclin A2/CDK2 and RB1, leading to an irreversible commitment to proliferation. Cornwell et al. (2023) demonstrated that mitogen signaling maintained CDK2 activity in S and G2 phases of the cell cycle, and that, in the absence of mitogen signaling, some post-R-point cells exited the cell cycle and entered a G0-like state instead of irreversibly committing to proliferation. Further analysis indicated that mitosis and cell cycle exit were 2 mutually exclusive fates, and that competition between the 2 determined whether cells continued to proliferate or exited the cell cycle. As a result, the decision to proliferate was fully reversible, even when cells were in post-R state, because CDK2 activation and RB1 phosphorylation were reversible in all post-R cells after loss of mitogen signaling. CDK4/CDK6 promoted cyclin A2 synthesis in S/G2, and cyclin A2 stability was the primary contributor to cell cycle exit. Cells were dependent on mitogens and CDK4/CDK6 activity to maintain CDK2 activity and RB1 phosphorylation throughout the cell cycle. The R-point irreversibility phenomenon was observed in the absence of mitogens, because in most cells, the half-life of cyclin A2 was long enough to sustain CDK2 activity throughout G2/M to reach mitosis. The results implied that there is no single point when cells are irreversibly committed to proliferation that can be defined by a single molecular event, but rather that it is determined by the cell's proximity to mitosis, as well as the cyclin A2 level when mitogen signaling is lost. </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>Evolution</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>Sivakumaran et al. (2005) conducted a comprehensive survey of sequence variation in the RB1 gene in diverse human populations and primates. A study of a wide range of ethnicities and 5 primate species indicated that nucleotide diversity of the coding region was 52 times lower than that of the noncoding regions, indicative of significant sequence conservation. The occurrence of purifying selection was corroborated by phylogeny-based maximum likelihood analysis of the RB1 sequences of human and 5 primates. RB1 displayed extensive linkage disequilibrium over 174 kb, and only 4 unique recombination events, 2 in Africa and 1 each in Europe and Southwest Asia, were observed. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Retinoblastoma</em></strong></p><p>
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Fung et al. (1987) used a cDNA probe to determine the lesion in retinoblastomas (180200). In 16 of 40 retinoblastomas studied with a cDNA probe by Fung et al. (1987), a structural change in the RB gene was identifiable, including, in some cases, homozygous internal deletions with corresponding truncated transcripts. An osteosarcoma also had a homozygous internal deletion with a truncated transcript. Possible hotspots for deletion were identified within the RB genomic locus. </p><p>Bookstein et al. (1988) identified at least 20 exons in genomic clones of the RB gene and provisionally numbered them. With a unique sequence probe from intron 1, they detected heterozygous deletions in genomic DNA from 3 retinoblastoma cell lines and genomic rearrangements in fibroblasts from 2 hereditary retinoblastoma patients, indicating that intron 1 includes a frequent site for mutations conferring predisposition to retinoblastoma. Demonstration of a DNA deletion of exons 2-6 from 1 RB allele, as well as the demonstration of other deletions, explains the origin of shortened RB mRNA transcripts. </p><p>Dunn et al. (1989) extended the characterization of mutations in RB1 using RNase protection of RB1 transcripts to locate probable mutations, followed by polymerase chain reaction (PCR) to amplify and sequence the mutant allele. Mutations were identified in 15 of 21 RB tumors; in 8 tumors, the precise error in nucleotide sequence was characterized. Each of 4 germline mutations involved a small deletion or duplication while 3 somatic mutations were point mutations leading to splice alterations and loss of an exon from the mature RB1 mRNA. </p><p>By PCR techniques, Yandell et al. (1989) demonstrated single nucleotide changes in tumors from 7 patients with simplex retinoblastoma (with no family history of the disease). In 4 patients, the mutation involved only the tumor cells, and in 3 it involved normal somatic cells as well as tumor cells but was not found in either parent. Thus, these 3 represent new germinal mutations. All 3 were C-to-T transitions in the coding strand in the retinoblastoma gene. Two of the 3 occurred at CpG pairs. </p><p>Lohmann et al. (1996) studied 119 patients with hereditary retinoblastoma for germline RB1 mutations. Southern blot hybridization and PCR fragment-length analysis revealed mutations in 48 patients. In the remaining 71 patients, they detected mutations in 51 (72%) by applying heteroduplex analysis, nonisotopic SSCP, and direct sequencing. Rare sequence variants were also found in 4 patients. No region of the RB1 gene was preferentially involved in single base substitutions. Recurrent transitions were observed at most of the 14 CGA codons within the RB1 gene. No mutation was observed in exons 25-27, although this region contains 2 CGA codons. This suggested to the authors that mutations within the 3-prime terminal region of the RB1 gene may not be oncogenic. For the entire series of 119 patients, mutations were identified in 99 (83%). The spectrum comprised 15% large deletions, 26% small length alterations, and 42% base substitutions. </p><p>Harbour (2001) stated that recent advances in understanding of the structure and function of the RB protein provided insights into the molecular basis of low-penetrance retinoblastoma. Low-penetrance retinoblastoma mutations either cause a reduction in the amount of normal RB that is produced (class 1 mutations) or result in a partially functional mutant RB (class 2 mutations). </p><p>Sampieri et al. (2006) identified mutations in the RB1 gene in 13 (37%) of 35 unrelated Italian patients with retinoblastoma. Mutations were identified in 6 of 9 familial cases and 7 of 26 sporadic cases. Eleven of the 13 mutations were novel. </p><p>Zhang et al. (2012) showed that the retinoblastoma genome is stable, but that multiple cancer pathways can be epigenetically deregulated. To identify the mutations that cooperate with RB1 loss in retinoblastoma, Zhang et al. (2012) performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. Zhang et al. (2012) then evaluated the role of RB1 in genome stability and considered nongenetic mechanisms of cancer pathway deregulation. For example, the protooncogene SYK (600085) is upregulated in retinoblastoma and is required for tumor cell survival. Targeting SYK with a small molecule inhibitor induced retinoblastoma tumor cell death in vitro and in vivo. Thus, Zhang et al. (2012) concluded that retinoblastomas may develop quickly as a result of the epigenetic deregulation of key cancer pathways as a direct or indirect result of RB1 loss. </p><p><strong><em>Small-Cell Lung Cancer</em></strong></p><p>
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|
Yokota et al. (1988) found markedly reduced amounts of RB transcript in some small-cell carcinomas (182280). </p><p>Hensel et al. (1988) found that all 3 patients with retinoblastoma whose DNA was heterozygous for a RFLP detected by an RB1 probe showed loss of 1 allele in DNA from small-cell lung cancer tissue.</p><p>Harbour et al. (1988) found structural abnormalities of the RB gene in 1 of 8 primary small-cell lung cancer tumors, in 4 of 22 small-cell lung cancer cell lines, and in 1 of 4 pulmonary carcinoid lines. RB mRNA was absent in 60% of SCLC lines and in 75% of pulmonary carcinoid lines, including all samples with DNA abnormalities. In contrast, RB transcripts were found in 90% of non-SCLC lines and in all normal human lung. It is of interest that both SCLC and pulmonary carcinoids are neuroendocrine tumors. </p><p>Horowitz et al. (1990) found that inactivation of the retinoblastoma protein, which is universal in retinoblastoma cells, is present in most small-cell lung cancers and in one-third of bladder cancers but is infrequent in other human tumors. </p><p><strong><em>Metastatic Cancer</em></strong></p><p>
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Robinson et al. (2017) performed whole-exome and transcriptome sequencing of 500 adult patients with metastatic solid tumors of diverse lineage and biopsy site. The most prevalent genes somatically altered in metastatic cancer included TP53 (191170), CDKN2A (600160), PTEN (601728), PIK3CA (171834), and RB1. Putative pathogenic germline variants were present in 12.2% of cases, of which 75% were related to defects in DNA repair. RNA sequencing complemented DNA sequencing to identify gene fusions, pathway activation, and immune profiling. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>28 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 RETINOBLASTOMA, 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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RB1, 1-BP DEL, 2657G
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<br />
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SNP: rs587776779,
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ClinVar: RCV000013944, RCV002426500
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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 tumor from a patient (RB-2) with bilateral retinoblastoma (180200), Yandell et al. (1989) identified heterozygosity for a 1-bp deletion (2657delG) in exon 24 (which codes for amino acid 840) in the RB1 gene, which caused a frameshift and a new stop codon in exon 25. This was a somatic mutation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0002 RETINOBLASTOMA, 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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RB1, IVS19, T-C, +2
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<br />
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SNP: rs587776780,
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ClinVar: RCV000013945
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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 tumor from a patient (RB-88) with unilateral retinoblastoma (180200), Yandell et al. (1989) identified a change of GT-to-GC at the first 2 nucleotides in the intron following exon 19 in the RB1 gene. Loss of the splice-donor site prevented normal splicing. The mutation was not found in the leukocytes of the patient or in the parents. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0003 RETINOBLASTOMA</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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|
RB1, ARG445TER
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<br />
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|
|
SNP: rs3092891,
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gnomAD: rs3092891,
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ClinVar: RCV000013946, RCV000492544, RCV002496351, RCV002508188
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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 the tumor of a patient (RB-74) with bilateral retinoblastoma (180200), Yandell et al. (1989) identified heterozygosity for a C-to-T transition at basepair 1462 in exon 14 of the RB1 gene, resulting in an arg445-to-ter substitution. This was a de novo germline mutation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0004 RETINOBLASTOMA</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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|
RB1, SER567LEU
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<br />
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SNP: rs137853292,
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ClinVar: RCV000013947, RCV004700228
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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 the tumor from a patient (RB-104) with bilateral retinoblastoma (180200), Yandell et al. (1989) identified a 1838C-T transition in exon 18 of the RB1 gene, resulting in a ser567-to-leu substitution. This represented homozygosity for a new germline mutation. </p>
|
|
</span>
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</div>
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<div>
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<br />
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|
</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0005 RETINOBLASTOMA</strong>
|
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</span>
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</h4>
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</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
RB1, ARG787TER
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|
<br />
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|
|
SNP: rs137853293,
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|
|
ClinVar: RCV000013948, RCV000492108, RCV000760351, RCV005007842
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|
|
</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In the tumor of a patient (RB-53) with bilateral retinoblastoma (180200), Yandell et al. (1989) identified a heterozygous 2498C-T transition in exon 23 of the RB1 gene, resulting in an arg787-to-ter substitution. This represented a new germline mutation. </p>
|
|
</span>
|
|
</div>
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|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 RETINOBLASTOMA, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
RB1, 1-BP DEL, 2381G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776781,
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|
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|
|
ClinVar: RCV000013949
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In the tumor of a patient (RB-45) with unilateral retinoblastoma (180200), Yandell et al. (1989) identified a 1-bp deletion (2381delG) in exon 22 of the RB1 gene, which led to a frameshift and creation of a new stop codon close by in exon 22. This was a somatic mutation present in heterozygous state in the tumor. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 RETINOBLASTOMA, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
RB1, IVS10, G-T, +1
|
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|
|
|
<br />
|
|
|
|
SNP: rs587776782,
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|
|
|
|
|
ClinVar: RCV000013950, RCV002399322
|
|
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|
|
|
</span>
|
|
</div>
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In the tumor from a patient (RB-119) with retinoblastoma (180200), Yandell et al. (1989) identified a G-to-T transversion in the first nucleotide in the intron following exon 10, which led to loss of a splice/donor site and prevented normal splicing. The mutation was somatic and heterozygous in the tumor. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
|
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 RETINOBLASTOMA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
RB1, ARG358TER
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs121913301,
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|
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|
|
ClinVar: RCV000013951, RCV000492492, RCV000725187, RCV004668727
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In cell line RB-W24 from a patient with retinoblastoma (180200), Yandell et al. (1989) identified a 1119C-T transition in exon 11 of the RB1 gene, resulting in an arg358-to-ter substitution. Yandell et al. (1989) could not characterize this mutation because normal somatic tissue was not available for study. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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<div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 BLADDER CANCER, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
RB1, IVS20, A-G, -2
|
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|
|
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<br />
|
|
|
|
SNP: rs1593538130,
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|
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|
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|
|
ClinVar: RCV000013952, RCV001229630, RCV004948134
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a bladder cancer (109800) tumor designated J82, Horowitz et al. (1989) found an A-to-G transition in the next to the last nucleotide in the intron 5-prime to exon 21 in the RB1 gene. Loss of splice-acceptor site prevented normal splicing.</p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 SMALL CELL CANCER OF THE LUNG, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
RB1, GLU748TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121913297,
|
|
|
|
|
|
|
|
ClinVar: RCV000013953, RCV002272016
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a small-cell lung cancer tumor (182280) designated H69, Yandell et al. (1989) identified a 2379G-T transversion in exon 22 of the RB1 gene, resulting in a glu748-to-ter substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 RETINOBLASTOMA, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
RB1, IVS12, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776783,
|
|
|
|
|
|
gnomAD: rs587776783,
|
|
|
|
|
|
ClinVar: RCV000114724, RCV000492136, RCV000763334, RCV003460796
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated patients with unilateral and unifocal retinoblastoma (RB571, RB600) (180200), Dunn et al. (1989) found identical somatic point mutations resulting in loss of exon 12. A frameshift introduced by the loss of exon 12 resulted in a truncated protein of 379 amino acids. A G-to-A transition at the splice donor site of exon 12 was responsible for aberrant splicing. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 RETINOBLASTOMA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
RB1, 5-BP DEL, EX8
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000013955
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>By RNase protection of the RB1 mRNA and sequencing of the PCR-cDNA in a patient (RB429) with bilateral retinoblastoma (180200). Dunn et al. (1989) identified a mutation in the RB1 gene: a 5-bp deletion in exon 8 causing a frameshift and a new termination codon in exon 8. The predicted truncated protein would contain 268 amino acids. Dunn et al. (1989) could not confirm that this was a germline mutation because constitutional cells from the patient were not available for study. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 RETINOBLASTOMA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
RB1, 55-BP DUP, EX10
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1555285429,
|
|
|
|
|
|
|
|
ClinVar: RCV000013956
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In the tumor of a patient (RB538) with retinoblastoma (180200), Dunn et al. (1989) identified a 55-bp duplication within exon 10 of the RB1 gene. A frameshift resulted in a new termination codon at position 346. This was a germline mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 RETINOBLASTOMA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
RB1, 10-BP DEL, EX18
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776784,
|
|
|
|
|
|
|
|
ClinVar: RCV000013957
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In the tumor of a patient (RB543) with retinoblastoma (180200), Dunn et al. (1989) identified a 10-bp deletion within exon 18 of the RB1 gene, causing a frameshift and a new termination codon. The predicted truncated protein would contain 586 amino acids. This was a germline mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 RETINOBLASTOMA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
RB1, 9-BP DEL, EX19
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776785,
|
|
|
|
|
|
|
|
ClinVar: RCV000013958
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In tumor RB470B from a patient (RB570) with retinoblastoma (180200), Dunn et al. (1989) demonstrated a 9-bp deletion in exon 19 of the RB1 gene, leading to a TAA termination codon. The predicted truncated protein would have 649 amino acids. This was a germline mutation. Different somatic mutations (614041.0016) were identified in 4 different tumors from this patient. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 RETINOBLASTOMA, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
RB1, EX22DEL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776786,
|
|
|
|
|
|
|
|
ClinVar: RCV000013959
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In patient RB570 with bilateral retinoblastoma who carried a 9-bp deletion in exon 19 of the RB1 gene as the germline mutation (614041.0015), Dunn et al. (1989) found a different somatic mutation in each of 4 separate tumors studied. These were 2 different LOH ('loss of heterozygosity') mutations, as indicated by RFLP studies, deletion of exon 22, and a tumor in which the exact nature of the change was not determined. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 RETINOBLASTOMA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
RB1, 189G-T, PROMOTER MUTATION
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906520,
|
|
|
|
|
|
|
|
ClinVar: RCV000013960
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Sakai et al. (1991) identified 2 mutations in the 5-prime region of the RB gene in patients with retinoblastoma (180200). One was a G-to-T transversion 189 bp 5-prime to the initiating methionine codon; the second was a G-to-A transition 198 bp upstream of the initiating methionine codon (614041.0018). The penetrance of these mutations appeared to be low; both carriers in 1 family had only unilateral retinoblastoma, and there were at least 3 obligate carriers who had no retinoblastoma in the second family. The mutation in the first family was within a sequence homologous to the consensus sequence for ATF, a transcription factor related or identical to CREB1 (123810). The second mutation was within a sequence similar to that recognized by SP1 (189906), a transcription factor with a zinc finger DNA-binding domain. Sakai et al. (1991) demonstrated that these natural mutants did not bind the transcription factors mentioned. The incomplete penetrance of the mutations may be related to the fact that the mutations result in a quantitative decrease in the expression of the RB gene, rather than in its complete inactivity. To develop into a retinoblastoma, it may be necessary for the retinal cell carrying one of these mutations to acquire a second, complete loss-of-function mutation of the homologous normal allele. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 RETINOBLASTOMA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
RB1, 198G-A, PROMOTER MUTATION
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906521,
|
|
|
|
|
|
|
|
ClinVar: RCV000013961, RCV000492684
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>See 614041.0017 and Sakai et al. (1991). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 RETINOBLASTOMA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
RB1, ARG661TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137853294,
|
|
|
|
|
|
gnomAD: rs137853294,
|
|
|
|
|
|
ClinVar: RCV000013962, RCV000492717, RCV000763335, RCV000790652, RCV004813036
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 families with an unusual low-penetrance phenotype of retinoblastoma (180200), with many individuals carrying the gene being unaffected, unilaterally affected, or with evidence of spontaneously regressed tumors, Onadim et al. (1992) found mutations in exon 20 of RB1. (Also see 614041.0020.) In 1 family, a C-to-T transition in codon 661 converted an arginine (CGG) to tryptophan (TGG) codon. The incomplete penetrance might indicate that this single amino acid change modified protein structure/function such that tumorigenesis was not inevitable. </p><p>Cowell and Bia (1998) pointed out that Lohmann et al. (1994) identified the same codon-661 mutation in 2 families with low penetrance. Cowell and Bia (1998) referred to their unpublished observations, identifying the same mutation in another family where both the 2 affected children and the unaffected father carried the arg661-to-trp (R661W) mutation. </p><p>Otterson et al. (1999) stated that 9 families with incomplete penetrance of familial retinoblastoma and carrying a R661W mutation had been reported. Their studies of this mutation demonstrated that the mutation is temperature-sensitive. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 RETINOBLASTOMA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
RB1, GLN675TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137853295,
|
|
|
|
|
|
|
|
ClinVar: RCV000013963
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>See 614041.0019. In a second family with incomplete penetrance of retinoblastoma (180200), Onadim et al. (1992) observed a G-to-T transversion in codon 675 that converted a glutamine (GAA) to a stop (TAA) codon. The mutation occurred near a potential cryptic splice acceptor site, raising the possibility of alternative splicing resulting in a less severely disrupted protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 RETINOBLASTOMA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
RB1, IVS21, G-A, -1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776787,
|
|
|
|
|
|
|
|
ClinVar: RCV000013964, RCV002426501
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Schubert et al. (1997) found a splicing mutation in a family with incomplete penetrance and variable expressivity of retinoblastoma (180200) as manifested by relatively late onset, unilaterality, and occurrence of unaffected carriers. Two RB1 cDNA products were identified by PCR: the wildtype product and a mutant cDNA that lacked exon 21. Sequence analysis of genomic DNA demonstrated a G-to-A transition at the last base of exon 21. The mutant allele did not change the amino acid code; both GAG and GAA encode glu. However, the alteration reduced the match of the exon boundary splice site to the consensus. Studies indicated that the mutation severely reduced correct splicing of the mutant mRNA but did not eliminate it. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 RETINOBLASTOMA, TRILATERAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
RB1, ARG556TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121913304,
|
|
|
|
|
|
|
|
ClinVar: RCV000013966, RCV000114734, RCV000492084
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a child with ectopic intracranial retinoblastoma, Onadim et al. (1997) found a nonsense mutation in exon 17 (codon 556) of the RB1 gene in homozygous (or hemizygous) state in both the retinal and the pineal tumors (180200). Diagnosis of bilateral retinoblastoma was made at the age of 13 months; the patient presented with the pineal tumor 32 months after the initial diagnosis of retinoblastoma. The RB1 mutation was a C-to-T transition (CGA to TGA) within a CpG dinucleotide, converting an arginine codon to a stop codon (R556X). The mutation occurred in a region of the gene that codes for part of the 'pocket' region of the Rb protein. The mutation was present heterozygously in the DNA from the constitutional cells of the patient. The mutation was absent in the blood DNA of both the father and the mother, and was shown to have occurred on the copy of the RB1 gene derived from the father. This mutation had been reported by Hogg et al. (1993) in the retinal tumor from a unilateral nonhereditary case of retinoblastoma. The same mutation was identified as a germline mutation by Cowell et al. (1994) and Liu et al. (1995). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 RETINOBLASTOMA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
RB1, 3-BP DEL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776788,
|
|
|
|
|
|
|
|
ClinVar: RCV000013967, RCV000492635
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Lohmann et al. (1994) described a germline del480 RB1 mutation (in-frame deletion of RB1 codon 480, resulting from a triplet nucleotide deletion) in affected members in a pedigree with retinoblastoma (180200) showing incomplete penetrance. Otterson et al. (1999) demonstrated that this mutation is temperature-sensitive. The disease-eye ratio (DER) score for this family was 1.0, with 5 obligate carriers: 1 unaffected, 3 with unilateral disease, and 1 with bilateral disease. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</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>.0024 RETINOBLASTOMA</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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RB1, CYS712ARG
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<br />
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SNP: rs137853296,
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ClinVar: RCV000013968, RCV000492516, RCV002466401
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In 2 separate previously reported families with incomplete penetrance of retinoblastoma (180200) and a cys712-to-arg (C712R) missense mutation in the RB1 gene, Otterson et al. (1999) found that the mutation was temperature-sensitive. </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>.0025 RETINOBLASTOMA</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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RB1, IVS6, G-T, +1
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<br />
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SNP: rs587776789,
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ClinVar: RCV000013969, RCV000484757, RCV000492204, RCV004795405
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 unrelated families with incomplete penetrance of retinoblastoma (180200), Klutz et al. (2002) found an IVS6+1G-T splice site mutation in the RB1 gene. Analysis of RNA from white blood cells showed that this mutation causes skipping of exon 6. Although the deletion resulted in a frameshift, most carriers of the mutation did not develop retinoblastoma. The relative abundance of the resultant nonsense mRNA varied between members of the same family and was either similar to or considerably lower than the transcript level of the normal allele. </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>.0026 RETINOBLASTOMA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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RB1, TYR606TER
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<br />
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SNP: rs137853297,
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ClinVar: RCV000013970, RCV002408459
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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>De Jong et al. (2006) described the documented growth, clinical course, and histopathology of retinoblastomas (180200) in an untreated and otherwise normal right eye of a 27-year-old white male with a g.153211T-A (tyr606-to-ter; W606X) mutation in the RB1 gene, whose left eye had been enucleated at age 2 years for 2 retinoblastomas. Despite extensive treatment, the right eye had to be removed due to tumor recurrences and seeding, pseudohypopyon, and elevated intraocular pressure. </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>.0027 RETINOBLASTOMA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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RB1, 23-BP DUP, NT43
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<br />
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|
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SNP: rs587776790,
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ClinVar: RCV000013971
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a large family with incomplete penetrance of retinoblastoma (180200), Sanchez-Sanchez et al. (2007) identified a 23-bp duplication in exon 1 of the RB1 gene, resulting in a frameshift and premature termination in exon 2. Only 3 (30%) of 10 mutation carriers were affected by disease. RT-PCR analysis showed that the mutation did not induce nonsense-mediated decay. Transcript expression in cultured cells showed that downstream alternative in-frame translation sites involving met113 and possibly met223 were used to generate N-terminal truncated RB1 products known and suspected to exhibit tumor suppressor activity. The findings suggested that modulation of disease penetrance in this family was achieved by internal translation initiation. </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>.0028 RETINOBLASTOMA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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RB1, IVS23AS, A-G, -1398
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<br />
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SNP: rs587776791,
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ClinVar: RCV000013972, RCV003321482
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 brothers with retinoblastoma (180200) diagnosed at age 2 years, Dehainault et al. (2007) identified a -1398A-G transition in intron 23 of the RB1 gene (IVS23AS-1398A-G), resulting in a 103-bp insertion between exons 23 and 24. In silico analysis demonstrated the creation of a cryptic splice site leading to an intronic sequence exonization. The unaffected father also carried the mutation, likely in a mosaic state. The mutation was not identified by point mutation or large rearrangement screening and was only detected by complete transcript analysis using RNA extracted from the patients' lymphoblastoid cells treated with puromycin. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</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>
|
|
<p class="mim-text-font">
|
|
Bookstein, R., Lee, E. Y.-H. P., To, H., Young, L.-J., Sery, T. W., Hayes, R. C., Friedmann, T., Lee, W.-H.
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<strong>Human retinoblastoma susceptibility gene: genomic organization and analysis of heterozygous intragenic deletion mutants.</strong>
|
|
Proc. Nat. Acad. Sci. 85: 2210-2214, 1988.
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<li>
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<p class="mim-text-font">
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|
Brown, V. D., Gallie, B. L.
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<strong>The B-domain lysine patch of pRB is required for binding to large T antigen and release of E2F by phosphorylation .</strong>
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Buchkovich, K., Duffy, L. A., Harlow, E.
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Cell 58: 1097-1105, 1989.
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Carreira, S., Goodall, J., Aksan, I., La Rocca, S. A., Galibert, M.-D., Denat, L., Larue, L., Goding, C. R.
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<strong>Mitf cooperates with Rb1 and activates p21(Cip1) expression to regulate cell cycle progression.</strong>
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Nature 433: 764-769, 2005.
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Cavenee, W. K.
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Trends Genet. 2: 299-300, 1986.
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Chano, T., Ikegawa, S., Kontani, K., Okabe, H., Baldini, N., Saeki, Y.
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<strong>Identification of RB1CC1, a novel human gene that can induce RB1 in various human cells.</strong>
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Oncogene 21: 1295-1298, 2002.
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[PubMed: 11850849]
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Chen, P.-L., Scully, P., Shew, J.-Y., Wang, J. Y. J., Lee, W.-H.
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<strong>Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentiation.</strong>
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Cell 58: 1193-1198, 1989.
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Cornwell, J. A., Crncec, A., Afifi, M. M., Tang, K., Amin, R., Cappell, S. D.
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<strong>Loss of CDK4/6 activity in S/G2 phase leads to cell cycle reversal.</strong>
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Nature 619: 363-370, 2023. Note: Erratum: Nature 630: E14, 2024.
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Cowell, J. K., Bia, B.
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Oncogene 16: 3211-3213, 1998.
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Cowell, J. K., Smith, T., Bia, B.
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Europ. J. Hum. Genet. 2: 281-290, 1994.
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Molec. Cell 8: 557-568, 2001. Note: Erratum: Molec. Cell 11: 1693-1696, 2003.
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de Jong, P. T. V. M., Mooy, C. M., Stoter, G., Eijkenboom, W. M. H., Luyten, G. P. M.
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<p class="mim-text-font">
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DeCaprio, J. A., Ludlow, J. W., Lynch, D., Furukawa, Y., Griffin, J., Piwnica-Worms, H., Huang, C.-M., Livingston, D. M.
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<strong>The product of the retinoblastoma susceptibility gene has properties of a cell cycle regulatory element.</strong>
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Cell 58: 1085-1095, 1989.
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[PubMed: 2673542]
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<p class="mim-text-font">
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Dehainault, C., Michaux, D., Pages-Berhouet, S., Caux-Moncoutier, V., Doz, F., Desjardins, L., Couturier, J., Parent, P., Stoppa-Lyonnet, D., Gauthier-Villars, M., Houdayer, C.
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<strong>A deep intronic mutation in the RB1 gene leads to intronic sequence exonisation.</strong>
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Europ. J. Hum. Genet. 15: 473-477, 2007.
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<p class="mim-text-font">
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Dryja, T., Cavenee, W., Epstein, J., Rapaport, J., Goorin, A., Koufos, A.
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Am. J. Hum. Genet. 36: 28S, 1984.
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Dryja, T. P., Friend, S., Weinberg, R. A.
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<strong>Isolation of a cDNA fragment derived from human retina mRNA which detects a locus within 13q14 often deleted in retinoblastomas. (Abstract)</strong>
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Am. J. Hum. Genet. 39: A29, 1986.
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Dunn, J. M., Phillips, R. A., Zhu, X., Becker, A., Gallie, B. L.
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<strong>Mutations in the RB1 gene and their effects on transcription.</strong>
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Molec. Cell. Biol. 9: 4596-4604, 1989.
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[PubMed: 2601691]
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[Full Text: https://doi.org/10.1128/mcb.9.11.4596-4604.1989]
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Fajas, L., Egler, V., Reiter, R., Hansen, J., Kristiansen, K., Debril, M.-B., Miard, S., Auwerx, J.
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Dev. Cell 3: 903-910, 2002.
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[PubMed: 12479814]
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Fearon, E. R.
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<strong>Human cancer syndromes: clues to the origin and nature of cancer.</strong>
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Science 278: 1043-1050, 1997.
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[PubMed: 9353177]
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[Full Text: https://doi.org/10.1126/science.278.5340.1043]
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<li>
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<p class="mim-text-font">
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Friend, S. H., Bernards, R., Rogelj, S., Weinberg, R. A., Rapaport, J. M., Albert, D. M., Dryja, T. P.
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<strong>A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma.</strong>
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Nature 323: 643-646, 1986.
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[PubMed: 2877398]
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[Full Text: https://doi.org/10.1038/323643a0]
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<li>
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<p class="mim-text-font">
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Fung, Y.-K. T., Murphree, A. L., T'Ang, A., Qian, J., Hinrichs, S. H., Benedict, W. F.
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<strong>Structural evidence for the authenticity of the human retinoblastoma gene.</strong>
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Science 236: 1657-1661, 1987.
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[PubMed: 2885916]
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[Full Text: https://doi.org/10.1126/science.2885916]
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</p>
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</li>
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<li>
|
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Bao Lige - updated : 02/08/2024<br>Ada Hamosh - updated : 10/29/2020<br>Ada Hamosh - updated : 12/19/2019<br>Ada Hamosh - updated : 01/29/2018<br>Matthew B. Gross - updated : 04/20/2016<br>Ada Hamosh - updated : 11/4/2014<br>Ada Hamosh - updated : 2/8/2012
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Carol A. Bocchini : 6/14/2011
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carol : 07/19/2024<br>mgross : 02/08/2024<br>mgross : 12/08/2020<br>mgross : 10/29/2020<br>alopez : 12/19/2019<br>carol : 11/25/2019<br>carol : 11/22/2019<br>carol : 11/21/2019<br>carol : 09/05/2019<br>carol : 01/30/2018<br>alopez : 01/29/2018<br>mgross : 04/20/2016<br>alopez : 11/4/2014<br>terry : 3/14/2013<br>alopez : 2/13/2012<br>terry : 2/8/2012<br>alopez : 9/23/2011<br>mgross : 6/21/2011<br>terry : 6/17/2011<br>carol : 6/17/2011<br>carol : 6/17/2011
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