6058 lines
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Entry
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- *600140 - CREB-BINDING PROTEIN; CREBBP
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- OMIM
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</form>
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*600140</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 role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#evolution">Evolution</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/600140">Table View</a>
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</li>
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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>
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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=ENSG00000005339;t=ENST00000262367" 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=1387" 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=600140" 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=ENSG00000005339;t=ENST00000262367" 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_001079846,NM_004380,XM_005255124,XM_005255125,XM_006720848,XM_011522381,XM_011522382,XM_017022944,XM_047433624,XM_047433625" 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_004380" 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=600140" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
|
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</div>
|
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
|
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</a>
|
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=02534&isoform_id=02534_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/CREBBP" 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/1888538,1888540,2443859,2996629,3168627,4321116,71052011,109941365,116241283,119605740,119605741,119605742,119605743,119943102,119943104,194358800,194358802,194358804,194358806,194358808,194358810,194358816,194358819,194358821,194358823,194358834,194358836,194358838,194358842,194358844,194358846,194358848,194358850,194358852,194358854,194358856,194358858,194358860,194358862,194358864,194358866,194358868,194358870,194358872,194358874,194358876,194358878,194358880,194358882,194358884,194358886,194358888,194358890,194358893,194358901,194358906,194358908,194358910,194358914,194388284,311643960,311643962,530407637,530407639,578827985,767986931,767986933,929654779,1034593644,2217304672,2217304674,2462547564,2462547566,2462547568,2462547570,2462547572,2462547574,2462547576" 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/Q92793" 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=1387" 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=ENSG00000005339;t=ENST00000262367" 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=CREBBP" 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=CREBBP" 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+1387" 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/CREBBP" 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:1387" 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/1387" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr16&hgg_gene=ENST00000262367.10&hgg_start=3725054&hgg_end=3880713&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:2348" 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:2348" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=600140[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=600140[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/CREBBP/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/ENSG00000005339" 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=CREBBP" 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=CREBBP" 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=CREBBP" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.LOVD.nl/CREBBP" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=CREBBP&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/PA26866" 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:2348" 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/FBgn0261617.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:1098280" 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/CREBBP#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:1098280" 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/1387/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=1387" 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=WBGene00000366;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-050208-439" 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:1387" 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=CREBBP&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
|
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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</div>
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<div>
|
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
|
600140
|
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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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CREB-BINDING PROTEIN; CREBBP
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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">
|
|
CBP
|
|
</span>
|
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</h4>
|
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</div>
|
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</div>
|
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<div>
|
|
<br />
|
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</div>
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<div>
|
|
<a id="includedTitles" class="mim-anchor"></a>
|
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<div>
|
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<p>
|
|
<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
CBP/MOZ FUSION GENE, INCLUDED
|
|
</span>
|
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</div>
|
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|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=CREBBP" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">CREBBP</a></em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/16/150?start=-3&limit=10&highlight=150">16p13.3</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr16:3725054-3880713&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">16:3,725,054-3,880,713</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=618332,180849" 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>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/16/150?start=-3&limit=10&highlight=150">
|
|
16p13.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Menke-Hennekam syndrome 1
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/618332"> 618332 </a>
|
|
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PheneGene Graphics <span class="caret"></span>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>When cellular levels of cAMP increase, a cascade of events leads to the induction of genes that contain cis-regulatory elements called cAMP-response elements (CREs). Elevated cAMP levels cause stimulation and nuclear translocation of protein kinase A (PKA; see <a href="/entry/176911">176911</a>), which activates the transcription factor CREB (CRE-binding protein; see <a href="/entry/123810">123810</a>) by phosphorylating it at a single residue, serine-133 (<a href="#19" class="mim-tip-reference" title="Gonzalez, G. A., Montminy, M. R. <strong>Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133.</strong> Cell 59: 675-680, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2573431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2573431</a>] [<a href="https://doi.org/10.1016/0092-8674(89)90013-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2573431">Gonzalez and Montminy, 1989</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2573431" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Chrivia, J. C., Kwok, R. P. S., Lamb, N., Hagiwara, M., Montminy, M. R., Goodman, R. H. <strong>Phosphorylated CREB binds specifically to the nuclear protein CBP.</strong> Nature 365: 855-859, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8413673/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8413673</a>] [<a href="https://doi.org/10.1038/365855a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8413673">Chrivia et al. (1993)</a> reported the discovery of a nuclear transcriptional coactivator protein, CREB-binding protein (CBP), that binds specifically to the PKA-phosphorylated form of the CREB protein. CBP is a large protein with a molecular mass of about 250 kD which contains a bromodomain, i.e., a conserved structural unit important for protein-protein interactions. In Drosophila and yeast, this domain is found in coactivator proteins involved in signal-dependent, but not basal, transcription (<a href="#35" class="mim-tip-reference" title="Nordheim, A. <strong>CREB takes CBP to tango.</strong> Nature 370: 177-178, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8028657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8028657</a>] [<a href="https://doi.org/10.1038/370177a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8028657">Nordheim, 1994</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8028657+8413673" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To isolate the gene responsible for Rubinstein-Taybi syndrome (RSTS1; <a href="/entry/180849">180849</a>), which is associated with breakpoints in and microdeletions of chromosome 16p13.3, <a href="#44" class="mim-tip-reference" title="Petrij, F., Giles, R. H., Dauwerse, H. G., Saris, J. J., Hennekam, R. C. M., Masuno, M., Tommerup, N., van Ommen, G.-J. B., Goodman, R. H., Peters, D. J. M., Breuning, M. H. <strong>Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP.</strong> Nature 376: 348-351, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7630403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7630403</a>] [<a href="https://doi.org/10.1038/376348a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7630403">Petrij et al. (1995)</a> used FISH to situate all RSTS breakpoints in an area of 150 kb, thus defining a candidate region. Complementary DNAs from this area showed very high sequence homology with mouse CBP. Further studies indicated that the human CBP gene spans at least the 150-kb genomic area containing the RSTS breakpoints. <a href="#18" class="mim-tip-reference" title="Giles, R. H., Petrij, F., Dauwerse, H. G., den Hollander, A. I., Lushnikova, T., van Ommen, G.-J. B., Goodman, R. H., Deaven, L. L., Doggett, N. A., Peters, D. J., Breuning, M. H. <strong>Construction of a 1.2-Mb contig surrounding, and molecular analysis of, the human CREB-binding protein (CBP/CREBBP) gene on chromosome 16p13.3.</strong> Genomics 42: 96-114, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9177780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9177780</a>] [<a href="https://doi.org/10.1006/geno.1997.4699" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9177780">Giles et al. (1997)</a> reported the cloning and sequencing of human CREBBP, which encodes a deduced 2,442-amino acid protein with a molecular mass of 265 kD with 95% homology to the mouse protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9177780+7630403" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#27" class="mim-tip-reference" title="Liu, X., Wang, L., Zhao, K., Thompson, P. R., Hwang, Y., Marmorstein, R., Cole, P. A. <strong>The structural basis of protein acetylation by the p300/CBP transcriptional coactivator.</strong> Nature 451: 846-850, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18273021/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18273021</a>] [<a href="https://doi.org/10.1038/nature06546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18273021">Liu et al. (2008)</a> described a high resolution x-ray crystal structure of a semisynthetic heterodimeric p300 (<a href="/entry/602700">602700</a>) HAT domain in complex with a bisubstrate inhibitor, Lys-CoA. This structure showed that p300/CBP is a distant cousin of other structurally characterized HATs, but revealed several novel features that explain the broad substrate specificity and preference for nearby basic residues. Based on this structure and accompanying biochemical data, <a href="#27" class="mim-tip-reference" title="Liu, X., Wang, L., Zhao, K., Thompson, P. R., Hwang, Y., Marmorstein, R., Cole, P. A. <strong>The structural basis of protein acetylation by the p300/CBP transcriptional coactivator.</strong> Nature 451: 846-850, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18273021/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18273021</a>] [<a href="https://doi.org/10.1038/nature06546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18273021">Liu et al. (2008)</a> proposed that p300/CBP uses an unusual hit-and-run (Theorell-Chance) catalytic mechanism that is distinct from other characterized HATs. Several disease-associated mutations could also be readily accounted for by the p300 HAT structure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18273021" 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="#44" class="mim-tip-reference" title="Petrij, F., Giles, R. H., Dauwerse, H. G., Saris, J. J., Hennekam, R. C. M., Masuno, M., Tommerup, N., van Ommen, G.-J. B., Goodman, R. H., Peters, D. J. M., Breuning, M. H. <strong>Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP.</strong> Nature 376: 348-351, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7630403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7630403</a>] [<a href="https://doi.org/10.1038/376348a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7630403">Petrij et al. (1995)</a> used FISH to show that mouse CBP hybridized to human 16p13.3. <a href="#10" class="mim-tip-reference" title="Chen, X.-N., Korenberg, J. R. <strong>Localization of human CREBBP (CREB binding protein) to 16p13.3 by fluorescence in situ hybridization.</strong> Cytogenet. Cell Genet. 71: 56-57, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7606928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7606928</a>] [<a href="https://doi.org/10.1159/000134062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7606928">Chen and Korenberg (1995)</a> also mapped CREBBP to 16p13.3 using a cDNA probe for the mouse gene in fluorescence in situ hybridization. Using a human genomic clone for FISH, <a href="#57" class="mim-tip-reference" title="Wydner, K. L., Bhattacharya, S., Eckner, R., Lawrence, J. B., Livingston, D. M. <strong>Localization of human CREB-binding protein gene (CREBBP) to 16p13.2-p13.3 by fluorescence in situ hybridization.</strong> Genomics 30: 395-396, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8586450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8586450</a>]" pmid="8586450">Wydner et al. (1995)</a> mapped CREBBP to 16p13.3-p13.2. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7606928+7630403+8586450" 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="#25" class="mim-tip-reference" title="Kwok, R. P. S., Lundblad, J. R., Chrivia, J. C., Richards, J. P., Bachinger, H. P., Brennan, R. G., Roberts, S. G. E., Green, M. R., Goodman, R. H. <strong>Nuclear protein CBP is a coactivator for the transcription factor CREB.</strong> Nature 370: 223-226, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7913207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7913207</a>] [<a href="https://doi.org/10.1038/370223a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7913207">Kwok et al. (1994)</a> used fluorescence anisotropy measurements to define the equilibrium binding parameters of the phosphoCREB:CBP interaction and reported that CBP can activate transcription through a region in its C terminus. The activation domain of CBP interacts directly with the basal transcription factor TFIIB (<a href="/entry/189963">189963</a>). As TFIIB interacts with the TATA-box-binding protein TBP1 (<a href="/entry/186852">186852</a>), a continuous chain of physical contacts is established linking the stimulus-activated phosphoCREB, bound distal to the promoter, with the polymerase II complex that initiates transcription (<a href="#35" class="mim-tip-reference" title="Nordheim, A. <strong>CREB takes CBP to tango.</strong> Nature 370: 177-178, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8028657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8028657</a>] [<a href="https://doi.org/10.1038/370177a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8028657">Nordheim, 1994</a>). Acting as a coactivator, CBP augments the activity of phosphorylated CREB to activate transcription of cAMP-responsive genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7913207+8028657" 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="#3" class="mim-tip-reference" title="Arias, J., Alberts, A. S., Brindle, P., Claret, F. X., Smeal, T., Karin, M., Feramisco, J., Montminy, M. <strong>Activation of cAMP and mitogen responsive genes relies on a common nuclear factor.</strong> Nature 370: 226-229, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8028671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8028671</a>] [<a href="https://doi.org/10.1038/370226a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8028671">Arias et al. (1994)</a> microinjected an anti-CBP antiserum into fibroblasts and determined that transcription from a cAMP promoter can be inhibited. <a href="#3" class="mim-tip-reference" title="Arias, J., Alberts, A. S., Brindle, P., Claret, F. X., Smeal, T., Karin, M., Feramisco, J., Montminy, M. <strong>Activation of cAMP and mitogen responsive genes relies on a common nuclear factor.</strong> Nature 370: 226-229, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8028671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8028671</a>] [<a href="https://doi.org/10.1038/370226a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8028671">Arias et al. (1994)</a> also reported that CBP cooperates with upstream activators, such as JUN (<a href="/entry/165160">165160</a>), that are involved in mitogen-responsive transcription. Studies indicated that when JUN was phosphorylated at the transcriptionally stimulatory sites ser73 and ser63, it bound CBP with comparable affinity to CREB. They proposed that CBP is recruited to the promoter through interaction with certain phosphorylated factors and that CBP may thus play a critical role in the transmission of inductive signals from cell surface receptors to the transcriptional apparatus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8028671" 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>Sterol regulatory element-binding proteins (SREBPs; e.g., <a href="/entry/184756">184756</a>) activate transcription of genes whose products are involved in the cellular uptake and synthesis of cholesterol. <a href="#37" class="mim-tip-reference" title="Oliner, J. D., Andresen, J. M., Hansen, S. K., Zhou, S., Tjian, R. <strong>SREBP transcriptional activity is mediated through an interaction with the CREB-binding protein.</strong> Genes Dev. 10: 2903-2911, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8918891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8918891</a>] [<a href="https://doi.org/10.1101/gad.10.22.2903" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8918891">Oliner et al. (1996)</a> showed that the putative activation domain of SREBP binds specifically to the N-terminal domains of recombinant CBP and p300 (EP300; <a href="/entry/602700">602700</a>), a CREBBP-related protein. Transfection studies demonstrated that CBP enhances the ability of SREBP to activate transcription of reporter genes in HeLa cells, thus suggesting that CBP may serve as a coactivator for SREBP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8918891" 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="#6" class="mim-tip-reference" title="Blobel, G. A., Nakajima, T., Eckner, R., Montminy, M., Orkin, S. H. <strong>CREB-binding protein cooperates with transcription factor GATA-1 and is required for erythroid differentiation.</strong> Proc. Nat. Acad. Sci. 95: 2061-2066, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9482838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9482838</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9482838[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.5.2061" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9482838">Blobel et al. (1998)</a> found that in mouse nonhematopoietic cells, Cbp stimulated Gata1 (<a href="/entry/305371">305371</a>) transcriptional activity. Cbp and Gata1 also coimmunoprecipitated from nuclear extracts of mouse erythroid cells. Interaction mapping pinpointed the contact sites to the zinc finger region of Gata1 and to the E1A-binding region of Cbp. Expression of adenovirus E1A revealed that the interaction of Cbp with Gata1 in erythroid cells affected differentiation and expression of endogenous Gata1 target genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9482838" 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="#55" class="mim-tip-reference" title="Weaver, B. K., Kumar, K. P., Reich, N. C. <strong>Interferon regulatory factor 3 and CREB-binding protein/p300 are subunits of double-stranded RNA-activated transcription factor DRAF1.</strong> Molec. Cell. Biol. 18: 1359-1368, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9488451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9488451</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9488451[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.18.3.1359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9488451">Weaver et al. (1998)</a> identified CREBBP/EP300 and IRF3 (<a href="/entry/603734">603734</a>) as components of DRAF1 (double-stranded RNA-activated factor-1), a positive regulator of interferon-stimulated gene transcription that functions as a direct response to viral infection. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9488451" 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="#26" class="mim-tip-reference" title="Lin, C. H., Hare, B. J., Wagner, G., Harrison, S. C., Maniatis, T., Fraenkel, E. <strong>A small domain of CBP/p300 binds diverse proteins: solution structure and functional studies.</strong> Molec. Cell 8: 581-590, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11583620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11583620</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00333-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11583620">Lin et al. (2001)</a> identified a compactly folded 46-residue domain in CBP and p300, the IRF3-binding domain (IBID), and determined its structure by nuclear magnetic resonance spectroscopy. IBID has a helical framework containing an apparently flexible polyglutamine loop that participates in ligand binding. Spectroscopic data indicated that induced folding accompanies association of IBID with its partners, which exhibit no evident sequence similarities. IBID is an important contributor to signal integration by CBP and p300. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11583620" 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>CBP binds to the ser133 phosphorylated region of CREB via a domain called KIX (<a href="#40" class="mim-tip-reference" title="Parker, D., Ferreri, K., Nakajima, T., LaMorte, V. J., Evans, R., Koerber, S. C., Hoeger, C., Montminy, M. R. <strong>Phosphorylation of CREB at ser-133 induces complex formation with CREB-binding protein via a direct mechanism.</strong> Molec. Cell. Biol. 16: 694-703, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8552098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8552098</a>] [<a href="https://doi.org/10.1128/MCB.16.2.694" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8552098">Parker et al., 1996</a>). The phosphorylated domain of CREB was termed KID for kinase-inducible domain. <a href="#45" class="mim-tip-reference" title="Radhakrishnan, I., Perez-Alvarado, G. C., Parker, D., Dyson, H. J., Montminy, M. R., Wright, P. E. <strong>Solution structure of the KIX domain of CBP bound to the transactivation domain of CREB: a model for activator:coactivator interactions.</strong> Cell 91: 741-752, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9413984/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9413984</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80463-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9413984">Radhakrishnan et al. (1997)</a> used nuclear magnetic resonance spectroscopy to study the molecular interactions of the KIX:KID domains of CBP and CREB, respectively. The KIX domain of CBP comprises amino acid residues 586 to 666. The KID domain of CREB comprises amino acid residues 101 to 160. The KID undergoes a coil-to-helix folding transition upon binding to KIX, forming 2 alpha helices. The amphipathic helix alpha-B of KID interacts with a hydrophobic groove defined by helices alpha-1 and alpha-3 of KIX. The other KID helix, alpha-A, contacts a different face of the alpha-3 helix. The phosphate group of the critical phosphoserine residue of KID forms a hydrogen bond to the side chain of tyr658 of KIX. The structure provides a model for interactions between other transactivation domains and their targets. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9413984+8552098" 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="McCampbell, A., Taylor, J. P., Taye, A. A., Robitschek, J., Li, M., Walcott, J., Merry, D., Chai, Y., Paulson, H., Sobue, G., Fischbeck, K. H. <strong>CREB-binding protein sequestration by expanded polyglutamine.</strong> Hum. Molec. Genet. 9: 2197-2202, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10958659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10958659</a>] [<a href="https://doi.org/10.1093/hmg/9.14.2197" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10958659">McCampbell et al. (2000)</a> demonstrated that CREB-binding protein is incorporated into nuclear inclusions formed by polyglutamine-containing proteins in cultured cells, transgenic mice, and tissue from patients with spinal and bulbar muscular atrophy (SBMA; <a href="/entry/313200">313200</a>). Soluble levels of CREB-binding protein were reduced in cells expressing expanded polyglutamine despite increased levels of CBP mRNA. Overexpression of CREBBP rescued cells from polyglutamine-mediated toxicity in neuronal cell culture. The authors proposed a CREBBP-sequestration model of polyglutamine expansion disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10958659" 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>Growth factors such as epidermal growth factor (EGF; <a href="/entry/131530">131530</a>) and insulin (<a href="/entry/176730">176730</a>) regulate development and metabolism via genes containing both POU homeodomain (PIT1; <a href="/entry/173110">173110</a>) and phorbol ester (AP1, or JNK) response elements. Although CBP functions as a coactivator on these elements, the mechanism of transactivation was unclear. <a href="#59" class="mim-tip-reference" title="Zanger, K., Radovick, S., Wondisford, F. E. <strong>CREB binding protein recruitment to the transcription complex requires growth factor-dependent phosphorylation of its GF box.</strong> Molec. Cell 7: 551-558, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11463380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11463380</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00202-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11463380">Zanger et al. (2001)</a> demonstrated that CBP is recruited to these elements only after it is phosphorylated at ser436 by growth factor-dependent signaling pathways. In contrast, p300, a protein closely related to CBP that lacks this phosphorylation site, binds only weakly to the transcription complex and in a growth factor-independent manner. A small region of CBP (amino acids 312 to 440), which the authors termed the GF box, contains a potent transactivation domain and mediates this effect. Direct phosphorylation represents a novel mechanism controlling coactivator recruitment to the transcription complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11463380" 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>To elucidate the molecular basis of assembling the multiprotein activation complex, <a href="#14" class="mim-tip-reference" title="Demarest, S. J., Martinez-Yamout, M., Chung, J., Chen, H., Xu, W., Dyson, H. J., Evans, R. M., Wright, P. E. <strong>Mutual synergistic folding in recruitment of CBP/p300 by p160 nuclear receptor coactivators.</strong> Nature 415: 549-553, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11823864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11823864</a>] [<a href="https://doi.org/10.1038/415549a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11823864">Demarest et al. (2002)</a> undertook a structural and thermodynamic analysis of the interaction domains of CBP and the activator for thyroid hormone and retinoid receptors (TRAM1; <a href="/entry/601937">601937</a>). <a href="#14" class="mim-tip-reference" title="Demarest, S. J., Martinez-Yamout, M., Chung, J., Chen, H., Xu, W., Dyson, H. J., Evans, R. M., Wright, P. E. <strong>Mutual synergistic folding in recruitment of CBP/p300 by p160 nuclear receptor coactivators.</strong> Nature 415: 549-553, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11823864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11823864</a>] [<a href="https://doi.org/10.1038/415549a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11823864">Demarest et al. (2002)</a> demonstrated that although the isolated domains are intrinsically disordered, they combine with high affinity to form a cooperatively folded helical heterodimer. The authors concluded that their study uncovers a unique mechanism, which they termed 'synergistic folding,' through which p160 coactivators recruit CBP to allow transmission of the hormone signal to the transcriptional machinery. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11823864" 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="#60" class="mim-tip-reference" title="Zhong, H., May, M. J., Jimi, E., Ghosh, S. <strong>The phosphorylation status of nuclear NF-kappa-B determines its association with CBP/p300 or HDAC-1.</strong> Molec. Cell 9: 625-636, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11931769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11931769</a>] [<a href="https://doi.org/10.1016/s1097-2765(02)00477-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11931769">Zhong et al. (2002)</a> demonstrated that transcriptionally inactive nuclear NFKB in resting cells consists of homodimers of either p65 (<a href="/entry/164014">164014</a>) or p50 (<a href="/entry/164011">164011</a>) complexed with the histone deacetylase HDAC1 (<a href="/entry/601241">601241</a>). Only the p50-HDAC1 complexes bound to DNA and suppressed NFKB-dependent gene expression in unstimulated cells. Appropriate stimulation caused nuclear localization of NFKB complexes containing phosphorylated p65 that associated with CBP and displaced the p50-HDAC1 complexes. These results demonstrated that phosphorylation of p65 determines whether it associates with either CBP or HDAC1, ensuring that only p65 entering the nucleus from cytoplasmic NFKB-IKB (<a href="/entry/164008">164008</a>) complexes can activate transcription. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11931769" 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>TDG (<a href="/entry/601423">601423</a>) initiates repair of G/T and G/U mismatches, commonly associated with CpG islands, by removing thymine and uracil moieties. <a href="#51" class="mim-tip-reference" title="Tini, M., Benecke, A., Um, S.-J., Torchia, J., Evans, R. M., Chambon, P. <strong>Association of CBP/p300 acetylase and thymine DNA glycosylase links DNA repair and transcription.</strong> Molec. Cell 9: 265-277, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11864601/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11864601</a>] [<a href="https://doi.org/10.1016/s1097-2765(02)00453-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11864601">Tini et al. (2002)</a> reported that TDG associates with transcriptional coactivators CBP and p300 (<a href="/entry/602700">602700</a>) and that the resulting complexes are competent for both the excision step of repair and histone acetylation. TDG stimulated CBP transcriptional activity in transfected cells and reciprocally served as a substrate for CBP/p300 acetylation. This acetylation triggered release of CBP from DNA ternary complexes and also regulated recruitment of repair endonuclease APE (<a href="/entry/107748">107748</a>). These observations revealed a potential regulatory role for protein acetylation in base mismatch repair and a role for CBP/p300 in maintaining genomic stability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11864601" 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>Huntington disease (HD; <a href="/entry/143100">143100</a>) belongs to the CAG repeat family of neurodegenerative diseases and is characterized by the presence of an expanded polyglutamine (polyQ) repeat in the huntingtin gene (HTT; <a href="/entry/613004">613004</a>). PolyQ-expanded htt accumulates within large aggregates that are found in various subcellular compartments, but are more often localized within the nucleus. It has been suggested that the sequestration of proteins essential to cell viability may be 1 mechanism that accounts for toxicity generated by polyQ-expanded proteins. Nuclear inclusions containing polyQ-expanded htt have been shown to recruit CREBBP. In a hippocampal cell line, <a href="#20" class="mim-tip-reference" title="Jiang, H., Nucifora, F. C., Jr., Ross, C. A., DeFranco, D. B. <strong>Cell death triggered by polyglutamine-expanded huntingtin in a neuronal cell line is associated with degradation of CREB-binding protein.</strong> Hum. Molec. Genet. 12: 1-12, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12490527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12490527</a>] [<a href="https://doi.org/10.1093/hmg/ddg002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12490527">Jiang et al. (2003)</a> found that toxicity within individual cells induced by polyQ-expanded htt (as revealed by a TUNEL assay) was associated with the localization of the mutant htt within either nuclear or perinuclear aggregates. However, in addition to CREBBP recruitment, CREBBP ubiquitylation and degradation were selectively enhanced by polyQ-expanded htt. <a href="#20" class="mim-tip-reference" title="Jiang, H., Nucifora, F. C., Jr., Ross, C. A., DeFranco, D. B. <strong>Cell death triggered by polyglutamine-expanded huntingtin in a neuronal cell line is associated with degradation of CREB-binding protein.</strong> Hum. Molec. Genet. 12: 1-12, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12490527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12490527</a>] [<a href="https://doi.org/10.1093/hmg/ddg002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12490527">Jiang et al. (2003)</a> concluded that selected substrates may be directed to the ubiquitin/proteasome-dependent protein degradation pathway in response to polyQ-expanded htt within the nucleus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12490527" 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="#52" class="mim-tip-reference" title="Tsuda, M., Takahashi, S., Takahashi, Y., Asahara, H. <strong>Transcriptional co-activators CREB-binding protein and p300 regulate chondrocyte-specific gene expression via association with Sox9.</strong> J. Biol. Chem. 278: 27224-27229, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12732631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12732631</a>] [<a href="https://doi.org/10.1074/jbc.M303471200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12732631">Tsuda et al. (2003)</a> found that SOX9 (<a href="/entry/608160">608160</a>) used CBP and p300 as transcriptional coactivators. SOX9 bound CBP and p300 in vitro and in vivo, and both coactivators enhanced SOX9-dependent COL2A1 (<a href="/entry/120140">120140</a>) promoter activity. Disruption of the CBP-SOX9 complex inhibited COL2A1 mRNA expression and differentiation of human mesenchymal stem cells into chondrocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12732631" 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>To determine the physiologic significance of the phosphorylation site at ser436 of the CREBBP protein, <a href="#61" class="mim-tip-reference" title="Zhou, X. Y., Shibusawa, N., Naik, K., Porras, D., Temple, K., Ou, H., Kaihara, K., Roe, M. W., Brady, M. J., Wondisford, F. E. <strong>Insulin regulation of hepatic gluconeogenesis through phosphorylation of CREB-binding protein.</strong> Nature Med. 10: 633-637, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15146178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15146178</a>] [<a href="https://doi.org/10.1038/nm1050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15146178">Zhou et al. (2004)</a> generated knockin mice containing a ser436-to-ala mutation. They demonstrated both in vitro and in vivo that the mutant CREBBP was aberrantly recruited to CREB protein, resulting in inappropriate activation of gluconeogenesis in the fed state and glucose intolerance resulting from increased hepatic glucose production. <a href="#61" class="mim-tip-reference" title="Zhou, X. Y., Shibusawa, N., Naik, K., Porras, D., Temple, K., Ou, H., Kaihara, K., Roe, M. W., Brady, M. J., Wondisford, F. E. <strong>Insulin regulation of hepatic gluconeogenesis through phosphorylation of CREB-binding protein.</strong> Nature Med. 10: 633-637, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15146178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15146178</a>] [<a href="https://doi.org/10.1038/nm1050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15146178">Zhou et al. (2004)</a> proposed that insulin signaling may directly regulate many cAMP signaling pathways at the transcriptional level by controlling CREBBP recruitment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15146178" 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="#53" class="mim-tip-reference" title="Turnell, A. S., Stewart, G. S., Grand, R. J. A., Rookes, S. M., Martin, A., Yamano, H., Elledge, S. J., Gallimore, P. H. <strong>The APC/C and CBP/p300 cooperate to regulate transcription and cell-cycle progression.</strong> Nature 438: 690-695, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16319895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16319895</a>] [<a href="https://doi.org/10.1038/nature04151" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16319895">Turnell et al. (2005)</a> showed that 2 anaphase-promoting complex/cyclosome (APC/C) components, APC5 (<a href="/entry/606948">606948</a>) and APC7 (<a href="/entry/606949">606949</a>), interact directly with the coactivators CBP and p300 through protein-protein interaction domains that are evolutionarily conserved in adenovirus E1A. This interaction stimulates intrinsic CBP/p300 acetyltransferase activity and potentiates CBP/p300-dependent transcription. <a href="#53" class="mim-tip-reference" title="Turnell, A. S., Stewart, G. S., Grand, R. J. A., Rookes, S. M., Martin, A., Yamano, H., Elledge, S. J., Gallimore, P. H. <strong>The APC/C and CBP/p300 cooperate to regulate transcription and cell-cycle progression.</strong> Nature 438: 690-695, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16319895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16319895</a>] [<a href="https://doi.org/10.1038/nature04151" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16319895">Turnell et al. (2005)</a> also showed that APC5 and APC7 suppress E1A-mediated transformation in a CBP/p300-dependent manner, indicating that these components of the APC/C may be targeted during cellular transformation. Furthermore, <a href="#53" class="mim-tip-reference" title="Turnell, A. S., Stewart, G. S., Grand, R. J. A., Rookes, S. M., Martin, A., Yamano, H., Elledge, S. J., Gallimore, P. H. <strong>The APC/C and CBP/p300 cooperate to regulate transcription and cell-cycle progression.</strong> Nature 438: 690-695, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16319895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16319895</a>] [<a href="https://doi.org/10.1038/nature04151" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16319895">Turnell et al. (2005)</a> established that CBP is required for APC/C function; specifically, gene ablation of CBP by RNA-mediated interference markedly reduces the E3 ubiquitin ligase activity of the APC/C and the progression of cells through mitosis. Taken together, <a href="#53" class="mim-tip-reference" title="Turnell, A. S., Stewart, G. S., Grand, R. J. A., Rookes, S. M., Martin, A., Yamano, H., Elledge, S. J., Gallimore, P. H. <strong>The APC/C and CBP/p300 cooperate to regulate transcription and cell-cycle progression.</strong> Nature 438: 690-695, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16319895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16319895</a>] [<a href="https://doi.org/10.1038/nature04151" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16319895">Turnell et al. (2005)</a> concluded that their results define discrete roles for the APC/C-CBP/p300 complexes in growth regulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16319895" 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="#54" class="mim-tip-reference" title="Wang, X., Arai, S., Song, X., Reichart, D., Du, K., Pascual, G., Tempst, P., Rosenfeld, M. G., Glass, C. K., Kurokawa, R. <strong>Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription.</strong> Nature 454: 126-130, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18509338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18509338</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18509338[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/nature06992" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18509338">Wang et al. (2008)</a> showed that an RNA-binding protein, TLS (<a href="/entry/137070">137070</a>), serves as a key transcriptional regulatory sensor of DNA damage signals that, on the basis of its allosteric modulation by RNA, specifically binds to and inhibits CBP and p300 histone acetyltransferase activities on a repressed gene target, cyclin D1 (CCND1; <a href="/entry/168461">168461</a>), in human cell lines. Recruitment of TLS to the CCND1 promoter to cause gene-specific repression is directed by single-stranded, low copy-number noncoding RNA (ncRNA) transcripts tethered to the 5-prime regulatory regions of CCND1 that are induced in response to DNA damage signals. <a href="#54" class="mim-tip-reference" title="Wang, X., Arai, S., Song, X., Reichart, D., Du, K., Pascual, G., Tempst, P., Rosenfeld, M. G., Glass, C. K., Kurokawa, R. <strong>Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription.</strong> Nature 454: 126-130, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18509338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18509338</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18509338[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/nature06992" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18509338">Wang et al. (2008)</a> suggested that signal-induced noncoding RNAs localized to regulatory regions of transcription units can act cooperatively as selective ligands, recruiting and modulating the activities of distinct classes of RNA-binding coregulators in response to specific signals, providing an unexpected noncoding RNA/RNA-binding protein-based strategy to integrate transcriptional programs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18509338" 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="#13" class="mim-tip-reference" title="Das, C., Lucia, M. S., Hansen, K. C., Tyler, J. K. <strong>CBP/p300-mediated acetylation of histone H3 on lysine56.</strong> Nature 459: 113-117, 2009. Note: Erratum: Nature 460: 1164 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19270680/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19270680</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19270680[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/nature07861" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19270680">Das et al. (2009)</a> demonstrated that the histone acetyltransferase CBP in flies, and CBP and p300 in humans, acetylate histone H3 on lys56 (H3K56), whereas Drosophila sir2 and human SIRT1 (<a href="/entry/604479">604479</a>) and SIRT2 (<a href="/entry/604480">604480</a>) deacetylate H3K56 acetylation. The histone chaperones ASF1A (<a href="/entry/609189">609189</a>) in humans and Asf1 in Drosophila are required for acetylation of H3K56 in vivo, whereas the histone chaperone CAF1 (see <a href="/entry/601245">601245</a>) in humans and Caf1 in Drosophila are required for the incorporation of histones bearing this mark into chromatin. <a href="#13" class="mim-tip-reference" title="Das, C., Lucia, M. S., Hansen, K. C., Tyler, J. K. <strong>CBP/p300-mediated acetylation of histone H3 on lysine56.</strong> Nature 459: 113-117, 2009. Note: Erratum: Nature 460: 1164 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19270680/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19270680</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19270680[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/nature07861" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19270680">Das et al. (2009)</a> showed that, in response to DNA damage, histones bearing acetylated K56 are assembled into chromatin in Drosophila and human cells, forming foci that colocalize with sites of DNA repair. Furthermore, acetylation of H3K56 is increased in multiple types of cancer, correlating with increased levels of ASF1A in these tumors. <a href="#13" class="mim-tip-reference" title="Das, C., Lucia, M. S., Hansen, K. C., Tyler, J. K. <strong>CBP/p300-mediated acetylation of histone H3 on lysine56.</strong> Nature 459: 113-117, 2009. Note: Erratum: Nature 460: 1164 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19270680/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19270680</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19270680[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/nature07861" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19270680">Das et al. (2009)</a> concluded that their identification of multiple proteins regulating the levels of H3K56 acetylation in metazoans will allow future studies of this critical and unique histone modification that couples chromatin assembly to DNA synthesis, cell proliferation, and cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19270680" 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="mim-changed mim-change"><p>Using genomewide sequencing methods in mouse cortical neurons, <a href="#23" class="mim-tip-reference" title="Kim, T.-K., Hemberg, M., Gray, J. M., Costa, A. M., Bear, D. M., Wu, J., Harmin, D. A., Laptewicz, M., Barbara-Haley, K., Kuersten, S., Markenscoff-Papadimitriou, E., Kuhl, D., Bito, H., Worley, P. F., Kreiman, G., Greenberg, M. E. <strong>Widespread transcription at neuronal activity-regulated enhancers.</strong> Nature 465: 182-187, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20393465/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20393465</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20393465[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/nature09033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20393465">Kim et al. (2010)</a> identified about 12,000 neuronal activity-regulated enhancers bound by Cbp in an activity-dependent manner. At thousands of enhancers, Cbp recruited RNA polymerase II (RNAPII; see <a href="/entry/180660">180660</a>). RNAPII transcribed bidirectionally a novel class of noncoding RNAs, enhancer RNAs (eRNAs), within enhancer domains defined by the presence of histone H3 (see <a href="/entry/602810">602810</a>) monomethylated at lys4. The level of eRNA expression at enhancers positively correlated with the level of mRNA synthesis at nearby genes, suggesting that eRNA synthesis occurs specifically at enhancers that are actively engaged in promoting mRNA synthesis. The authors proposed that their findings reveal a novel mechanism of enhancer activation involving CBP, RNAPII, and eRNA synthesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20393465" 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></div>
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<p>In certain human cancers, the expression of critical oncogenes is driven from large regulatory elements called superenhancers, which recruit much of the cell's transcriptional apparatus and are defined by extensive acetylation of histone H3 lysine-27 (H3K27ac). <a href="#29" class="mim-tip-reference" title="Mansour, M. R., Abraham, B. J., Anders, L., Berezovskaya, A., Gutierrez, A., Durbin, A. D., Etchin, J., Lawton, L., Sallan, S. E., Silverman, L. B., Loh, M. L., Hunger, S. P., Sanda, T., Young, R. A., Look, A. T. <strong>An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element.</strong> Science 346: 1373-1377, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25394790/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25394790</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25394790[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.1259037" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25394790">Mansour et al. (2014)</a> found that, in a subset of T-ALL cases, heterozygous somatic indels are acquired that introduce binding motifs for the MYB (<a href="/entry/189990">189990</a>) transcription factor in a precise noncoding site, which creates a superenhancer 7.5 kb upstream of the TAL1 (<a href="/entry/187040">187040</a>) oncogene. Indels at this site were referred to as 'mutation of the TAL1 enhancer,' or MuTE. MYB binds to the new site introduced by MuTE and recruits its H3K27 acetylase-binding partner CBP, as well as core components of a major leukemogenic transcriptional complex that contains RUNX1 (<a href="/entry/151385">151385</a>), GATA3 (<a href="/entry/131320">131320</a>), and TAL1 itself. Additionally, most endogenous superenhancers found in T-ALL cells are occupied by MYB and CBP, which suggests a general role for MYB in superenhancer initiation. <a href="#29" class="mim-tip-reference" title="Mansour, M. R., Abraham, B. J., Anders, L., Berezovskaya, A., Gutierrez, A., Durbin, A. D., Etchin, J., Lawton, L., Sallan, S. E., Silverman, L. B., Loh, M. L., Hunger, S. P., Sanda, T., Young, R. A., Look, A. T. <strong>An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element.</strong> Science 346: 1373-1377, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25394790/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25394790</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25394790[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.1259037" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25394790">Mansour et al. (2014)</a> estimated that MuTE abnormalities account for about half of the cases with unexplained monoallelic overexpression of TAL1. <a href="#29" class="mim-tip-reference" title="Mansour, M. R., Abraham, B. J., Anders, L., Berezovskaya, A., Gutierrez, A., Durbin, A. D., Etchin, J., Lawton, L., Sallan, S. E., Silverman, L. B., Loh, M. L., Hunger, S. P., Sanda, T., Young, R. A., Look, A. T. <strong>An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element.</strong> Science 346: 1373-1377, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25394790/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25394790</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25394790[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.1259037" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25394790">Mansour et al. (2014)</a> concluded that this study identified a genetic mechanism responsible for the generation of oncogenic superenhancers in malignant cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25394790" 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>Rubinstein-Taybi Syndrome 1</em></strong></p><p>
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<a href="#44" class="mim-tip-reference" title="Petrij, F., Giles, R. H., Dauwerse, H. G., Saris, J. J., Hennekam, R. C. M., Masuno, M., Tommerup, N., van Ommen, G.-J. B., Goodman, R. H., Peters, D. J. M., Breuning, M. H. <strong>Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP.</strong> Nature 376: 348-351, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7630403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7630403</a>] [<a href="https://doi.org/10.1038/376348a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7630403">Petrij et al. (1995)</a> found that all the breakpoints and microdeletions in Rubinstein-Taybi syndrome are located in 16p13.3, in a region containing the CREBBP gene. They showed, furthermore, that RSTS results not only from gross chromosomal rearrangements of 16p but also from heterozygous point mutations in the CBP gene itself (see, e.g., <a href="#0001">600140.0001</a>), suggesting that the loss of one functional copy of the CBP gene underlies the developmental abnormalities in RSTS, and possibly the propensity for malignancy and keloid formation. To search for mutations in RSTS patients without rearrangements, <a href="#44" class="mim-tip-reference" title="Petrij, F., Giles, R. H., Dauwerse, H. G., Saris, J. J., Hennekam, R. C. M., Masuno, M., Tommerup, N., van Ommen, G.-J. B., Goodman, R. H., Peters, D. J. M., Breuning, M. H. <strong>Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP.</strong> Nature 376: 348-351, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7630403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7630403</a>] [<a href="https://doi.org/10.1038/376348a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7630403">Petrij et al. (1995)</a> used the protein truncation test. In 2 of 16 patients, a truncated protein product was found; both patients, who had classic RSTS phenotype, had a change of a glutamine codon to a stop codon (see <a href="#0001">600140.0001</a> and <a href="#0002">600140.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7630403" 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="Taine, L., Goizet, C., Wen, Z. Q., Petrij, F., Breuning, M. H., Ayme, S., Saura, R., Arveiler, B., Lacombe, D. <strong>Submicroscopic deletion of chromosome 16p13.3 in patients with Rubinstein-Taybi syndrome.</strong> Am. J. Med. Genet. 78: 267-270, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9677064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9677064</a>]" pmid="9677064">Taine et al. (1998)</a> found microdeletion of the RT1 probe (D16S237) in 3 of 30 French patients with RSTS. By pooling data from their study and previous series, they found the cumulative frequency of the 16p13.3 microdeletion to be 11.9% (19 in 159). Most reported microdeletions of the CREBBP gene in RSTS had been detected by FISH with a single cosmid probe specific to the 3-prime region of the gene. To explore the possibility that the rate of microdeletion-positive cases would be greater if the entire gene were evaluated, <a href="#7" class="mim-tip-reference" title="Blough, R. I., Petrij, F., Dauwerse, J. G., Milatovich-Cherry, A., Weiss, L., Saal, H. M., Rubinstein, J. H. <strong>Variation in microdeletions of the cyclic AMP-responsive element-binding protein gene at chromosome band 16p13.3 in the Rubinstein-Taybi syndrome.</strong> Am. J. Med. Genet. 90: 29-34, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10602114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10602114</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(20000103)90:1<29::aid-ajmg6>3.0.co;2-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10602114">Blough et al. (2000)</a> performed FISH on 66 patients with an established diagnosis of RSTS, using a panel of 5 cosmids spanning the CREBBP gene. Five of the 66 patients had deletions by FISH (9%), consistent with those rates reported in various series that ranged between 3% and 25%. The findings of a partial 5-prime deletion and of interstitial deletions of the gene added to the known spectrum of mutations and demonstrated the need for evaluation of the entire CREBBP gene in RSTS patients. No phenotypic differences between partial deletion, complete deletion, and nondeletion patients were observed, supporting a haploinsufficiency model for this disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10602114+9677064" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#42" class="mim-tip-reference" title="Petrij, F., Dauwerse, H. G., Blough, R. I., Giles, R. H., van der Smagt, J. J., Wallerstein, R., Maaswinkel-Mooy, P. D., van Karnebeek, C. D., van Ommen, G.-J. B., van Haeringen, A., Rubinstein, J. H., Saal, H. M., Hennekam, R. C. M., Peters, D. J. M., Breuning, M. H. <strong>Diagnostic analysis of the Rubinstein-Taybi syndrome: five cosmids should be used for microdeletion detection and low number of protein truncating mutations.</strong> J. Med. Genet. 37: 168-176, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10699051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10699051</a>] [<a href="https://doi.org/10.1136/jmg.37.3.168" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10699051">Petrij et al. (2000)</a> reported diagnostic analysis of 194 patients with RSTS. Of these, 86 had previously been reported. A total of 157 individuals were tested by FISH, 23 by protein truncation test, and 14 by both methods for microdeletions and truncating mutations in CBP. Fourteen of 171 (8.2%) patients had microdeletions. Eighty-nine of the 171 were tested using 5 cosmid probes: RT1, RT100, RT102, RT191, RT203 and RT166. Eight microdeletions were found in this group, of which 4 were not deleted for RT1/RT100. <a href="#42" class="mim-tip-reference" title="Petrij, F., Dauwerse, H. G., Blough, R. I., Giles, R. H., van der Smagt, J. J., Wallerstein, R., Maaswinkel-Mooy, P. D., van Karnebeek, C. D., van Ommen, G.-J. B., van Haeringen, A., Rubinstein, J. H., Saal, H. M., Hennekam, R. C. M., Peters, D. J. M., Breuning, M. H. <strong>Diagnostic analysis of the Rubinstein-Taybi syndrome: five cosmids should be used for microdeletion detection and low number of protein truncating mutations.</strong> J. Med. Genet. 37: 168-176, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10699051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10699051</a>] [<a href="https://doi.org/10.1136/jmg.37.3.168" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10699051">Petrij et al. (2000)</a> concluded that the use of all 5 probes is essential to detect all microdeletions in patients with clinical features of RSTS. The protein truncation test revealed truncating mutations in 4 of 37 (10.8%) cases. <a href="#42" class="mim-tip-reference" title="Petrij, F., Dauwerse, H. G., Blough, R. I., Giles, R. H., van der Smagt, J. J., Wallerstein, R., Maaswinkel-Mooy, P. D., van Karnebeek, C. D., van Ommen, G.-J. B., van Haeringen, A., Rubinstein, J. H., Saal, H. M., Hennekam, R. C. M., Peters, D. J. M., Breuning, M. H. <strong>Diagnostic analysis of the Rubinstein-Taybi syndrome: five cosmids should be used for microdeletion detection and low number of protein truncating mutations.</strong> J. Med. Genet. 37: 168-176, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10699051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10699051</a>] [<a href="https://doi.org/10.1136/jmg.37.3.168" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10699051">Petrij et al. (2000)</a> concluded that microdeletions and truncating mutations in CBP account for approximately 20% of mutations in individuals with the RSTS phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10699051" 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="#43" class="mim-tip-reference" title="Petrij, F., Dorsman, J. C., Dauwerse, H. G., Giles, R. H., Peeters, T., Hennekam, R. C. M., Breuning, M. H., Peters, D. J. M. <strong>Rubinstein-Taybi syndrome caused by a de novo reciprocal translocation t(2;16)(q36.3;p13.3).</strong> Am. J. Med. Genet. 92: 47-52, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10797422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10797422</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(20000501)92:1<47::aid-ajmg8>3.0.co;2-h" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10797422">Petrij et al. (2000)</a> stated that the breakpoints of 6 translocations and inversions described in RSTS patients clustered in a 13-kb intronic region at the 5-prime end of the CBP gene and could theoretically result only in proteins containing the extreme N-terminal region of CREB-binding protein. Microdeletions had occurred more frequently, in approximately 10% of cases. In contrast to the previous findings, <a href="#43" class="mim-tip-reference" title="Petrij, F., Dorsman, J. C., Dauwerse, H. G., Giles, R. H., Peeters, T., Hennekam, R. C. M., Breuning, M. H., Peters, D. J. M. <strong>Rubinstein-Taybi syndrome caused by a de novo reciprocal translocation t(2;16)(q36.3;p13.3).</strong> Am. J. Med. Genet. 92: 47-52, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10797422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10797422</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(20000501)92:1<47::aid-ajmg8>3.0.co;2-h" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10797422">Petrij et al. (2000)</a> showed that in one patient with a translocation t(2;16)(q36.3;p13.3), the chromosome 16 breakpoint was located about 100 kb downstream of the previously identified breakpoint cluster. Fiber FISH and Southern blot analysis were used in this determination. Western blot analysis of extracts prepared from lymphoblasts showed both a normal and an abnormal shorter protein lacking the C-terminal domain, indicating expression of both the normal and the mutant allele. The results suggested that the loss of C-terminal domains of the protein product is sufficient to cause RSTS. Furthermore, the data indicated the potential utility of Western blot analysis as an inexpensive and fast approach for screening RSTS mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10797422" 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="Murata, T., Kurokawa, R., Krones, A., Tatsumi, K., Ishii, M., Taki, T., Masuno, M., Ohashi, H., Yanagisawa, M., Rosenfeld, M. G., Glass, C. K., Hayashi, Y. <strong>Defect of histone acetyltransferase activity of the nuclear transcriptional coactivator CBP in Rubinstein-Taybi syndrome.</strong> Hum. Molec. Genet. 10: 1071-1076, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11331617/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11331617</a>] [<a href="https://doi.org/10.1093/hmg/10.10.1071" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11331617">Murata et al. (2001)</a> analyzed the CBP gene in 16 RSTS patients. A microdeletion was identified in 1 patient by FISH analysis; heteroallelic mutations were identified in 5 patients. These included a 2-bp and an 11-bp deletion, a 14-bp insertion, and a missense mutation resulting in an arg1378-to-pro substitution (<a href="#0003">600140.0003</a>). This missense mutation was introduced into the recombinant mouse CBP, where it abolished the HAT activity of CBP and the ability of CBP to transactivate CREB. The authors hypothesized that loss of HAT activity of CBP may cause RSTS. They further speculated that treatment of RSTS patients with histone deacetylase inhibitors might have beneficial effects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11331617" 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>Among 63 patients with RSTS, <a href="#12" class="mim-tip-reference" title="Coupry, I., Roudaut, C., Stef, M., Delrue, M.-A., Marche, M., Burgelin, I., Taine, L., Cruaud, C., Lacombe, D., Arveiler, B. <strong>Molecular analysis of the CBP gene in 60 patients with Rubinstein-Taybi syndrome.</strong> J. Med. Genet. 39: 415-421, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12070251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12070251</a>] [<a href="https://doi.org/10.1136/jmg.39.6.415" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12070251">Coupry et al. (2002)</a> used several molecular techniques, including cDNA probes to search for gross gene rearrangements, intragenic microsatellite markers, and PCR with direct sequencing, to identify 22 novel point mutations in the CBP gene. In 33 patients, no abnormality in the CBP gene was detected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12070251" 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="#21" class="mim-tip-reference" title="Kalkhoven, E., Roelfsema, J. H., Teunissen, H., den Boer, A., Ariyurek, Y., Zantema, A., Breuning, M. H., Hennekam, R. C. M., Peters, D. J. M. <strong>Loss of CBP acetyltransferase activity by PHD finger mutations in Rubinstein-Taybi syndrome.</strong> Hum. Molec. Genet. 12: 441-450, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12566391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12566391</a>] [<a href="https://doi.org/10.1093/hmg/ddg039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12566391">Kalkhoven et al. (2003)</a> performed mutational analysis in 39 RSTS patients and identified 8 heterozygous mutations in the HAT domain of CBP, one of which altered a conserved plant homeodomain (PHD) zinc finger amino acid (E1278K; <a href="#0006">600140.0006</a>), while a second deleted exon 22 (<a href="#0007">600140.0007</a>), which encodes the central region of the PHD finger. Functional analysis revealed that these PHD finger mutants lacked in vitro acetyltransferase activity towards histones and CBP itself and displayed reduced coactivator function for the transcription factor CREB. In EBV-transformed lymphoblastoid cells from the exon 22 deletion patient, there was 50% less endogenous CBP HAT activity. The authors stressed the functional importance of the PHD finger in vivo, and implied that reduction of CBP HAT activity, as exemplified by disruption of the PHD finger, may be sufficient to cause RSTS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12566391" 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 6 (28.6%) of 21 RSTS patients in whom no point mutations had been identified, <a href="#47" class="mim-tip-reference" title="Stef, M., Simon, D., Mardirossian, B., Delrue, M.-A., Burgelin, I., Hubert, C., Marche, M., Bonnet, F., Gorry, P., Longy, M., Lacombe, D., Coupry, I., Arveiler, B. <strong>Spectrum of CREBBP gene dosage anomalies in Rubinstein-Taybi syndrome patients.</strong> Europ. J. Hum. Genet. 15: 843-847, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17473832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17473832</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201847" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17473832">Stef et al. (2007)</a> used comparative genomic hybridization on microarrays and quantitative multiplex fluorescent-PCR to identify deletions involving the CREBBP gene. The deletions ranged in size from 3.3 kb to 6.5 Mb; 1 patient had a deleterious duplication containing exon 16. No phenotypic differences were observed, except for 1 patient with a 6.5-Mb deletion, who had a severe phenotype and died at 34 days of life. <a href="#47" class="mim-tip-reference" title="Stef, M., Simon, D., Mardirossian, B., Delrue, M.-A., Burgelin, I., Hubert, C., Marche, M., Bonnet, F., Gorry, P., Longy, M., Lacombe, D., Coupry, I., Arveiler, B. <strong>Spectrum of CREBBP gene dosage anomalies in Rubinstein-Taybi syndrome patients.</strong> Europ. J. Hum. Genet. 15: 843-847, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17473832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17473832</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201847" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17473832">Stef et al. (2007)</a> concluded that CREBBP dosage anomalies constitute a common cause of the disorder and recommended high-resolution gene dosage studies of the CREBBP gene in candidate patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17473832" 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="#16" class="mim-tip-reference" title="Gervasini, C., Castronovo, P., Bentivegna, A., Mottadelli, F., Faravelli, F., Giovannucci-Uzielli, M. L., Pessagno, A., Lucci-Cordisco, E., Pinto, A. M., Salviati, L., Selicorni, A., Tenconi, R., Neri, G., Larizza, L. <strong>High frequency of mosaic CREBBP deletions in Rubinstein-Taybi syndrome patients and mapping of somatic and germ-line breakpoints.</strong> Genomics 90: 567-573, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17855048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17855048</a>] [<a href="https://doi.org/10.1016/j.ygeno.2007.07.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17855048">Gervasini et al. (2007)</a> used FISH and microsatellite analysis to screen 42 Italian RSTS patients and identified deletions involving the CREBBP gene that ranged in size from 150 kb to 2.6 Mb in 6 patients. Three of the patients were low-level mosaics, with the deletion present in less than 30% of lymphocytes and in less than 20% of epithelial cells analyzed. The authors noted that, despite the small number of deleted cells in the investigated tissues, the clinical phenotype of the mosaic patients was quite typical, thus emphasizing the dose sensitivity of CREBBP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17855048" 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>Menke-Hennekam Syndrome 1</em></strong></p><p>
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<a href="#32" class="mim-tip-reference" title="Menke, L. A., van Belzen, M. J., Alders, M., Cristofoli, F., DDD Study, Ehmke, N., Fergelot, P., Foster, A., Gerkes, E. H., Hoffer, M. J. V., Horn, D., Kant, S. G., and 12 others. <strong>CREBBP mutations in individuals without Rubinstein-Taybi syndrome phenotype.</strong> Am. J. Med. Genet. 170A: 2681-2693, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27311832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27311832</a>] [<a href="https://doi.org/10.1002/ajmg.a.37800" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27311832">Menke et al. (2016)</a> reported 10 novel missense variants (e.g., <a href="#0009">600140.0009</a>-<a href="#0012">600140.0012</a>) in CREBBP, all in the last part of exon 30 or the first part of exon 31, in 11 patients with Menke-Hennekam syndrome. All mutations occurred de novo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27311832" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Menke, L. A., DDD Study, Gardeitchik, T., Hammond, P., Heimdal, K. R., Houge, G., Hufnagel, S. B., Ji, J., Johansson, S., Kant, S. G., Kinning, E., Leon, E. L., and 14 others. <strong>Further delineation of an entity caused by CREBBP and EP300 mutations but not resembling Rubinstein-Taybi syndrome.</strong> Am. J. Med. Genet. 176: 862-876, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29460469/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29460469</a>] [<a href="https://doi.org/10.1002/ajmg.a.38626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29460469">Menke et al. (2018)</a> reported 9 different mutations (e.g., <a href="#0010">600140.0010</a>-<a href="#0012">600140.0012</a>), 6 of them novel, in exon 30 or 31 of the CREBBP gene in 11 previously unreported patients with MKHK1. Eight mutations were missense and 1 was a 3-bp deletion; all but 1, in a patient whose parents were deceased, were shown to have occurred de novo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29460469" 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="Angius, A., Uva, P., Oppo, M., Persico, I., Onano, S., Olla, S., Pes, V., Perria, C., Cuccuru, G., Atzeni, R., Serra, G., Cucca, F., Sotgiu, S., Hennekam, R. C., Crisponi, L. <strong>Confirmation of a new phenotype in an individual with a variant in the last part of exon 30 of CREBBP.</strong> Am. J. Med. Genet. 179A: 634-638, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30737887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30737887</a>] [<a href="https://doi.org/10.1002/ajmg.a.61052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30737887">Angius et al. (2019)</a> reported an additional patient with a novel de novo missense variant (E1724K; <a href="#0013">600140.0013</a>) in exon 30 of CREBBP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30737887" 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>Chromosome 16p13.3 Duplication Syndrome</em></strong></p><p>
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<a href="#50" class="mim-tip-reference" title="Thienpont, B., Bena, F., Breckpot, J., Philip, N., Menten, B., Van Esch, H., Scalais, E., Salamone, J. M., Fong, C. T., Kussmann, J. L., Grange, D. K., Gorski, J. L., and 12 others. <strong>Duplications of the critical Rubinstein-Taybi deletion region on chromosome 16p13.3 cause a novel recognisable syndrome.</strong> J. Med. Genet. 47: 155-161, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19833603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19833603</a>] [<a href="https://doi.org/10.1136/jmg.2009.070573" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19833603">Thienpont et al. (2010)</a> reported 12 unrelated patients with mild to moderate mental retardation and mild skeletal anomalies associated with interstitial duplication of chromosome 16p13.3 (<a href="/entry/613458">613458</a>). Ten of the 12 duplications occurred de novo, and 2 were inherited from unaffected parents. The duplications ranged in size, but the smallest region of overlap was 186 to 260 kb in size and included the CREBBP gene. None of the breakpoints were recurrent, arguing against nonallelic homologous recombination as a mechanism. The findings indicated that CREBBP is dosage-sensitive. <a href="#50" class="mim-tip-reference" title="Thienpont, B., Bena, F., Breckpot, J., Philip, N., Menten, B., Van Esch, H., Scalais, E., Salamone, J. M., Fong, C. T., Kussmann, J. L., Grange, D. K., Gorski, J. L., and 12 others. <strong>Duplications of the critical Rubinstein-Taybi deletion region on chromosome 16p13.3 cause a novel recognisable syndrome.</strong> J. Med. Genet. 47: 155-161, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19833603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19833603</a>] [<a href="https://doi.org/10.1136/jmg.2009.070573" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19833603">Thienpont et al. (2010)</a> estimated the frequency of CREBBP duplication to be 1 in 97,000 to 146,000 live births. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19833603" 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>Non-Hodgkin Lymphoma</em></strong></p><p>
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<a href="#41" class="mim-tip-reference" title="Pasqualucci, L., Dominguez-Sola, D., Chiarenza, A., Fabbri, G., Grunn, A., Trifonov, V., Kasper, L. H., Lerach, S., Tang, H., Ma, J., Rossi, D., Chadburn, A., Murty, V. V., Mullighan, C. G., Gaidano, G., Rabadan, R., Brindle, P. K., Dalla-Favera, R. <strong>Inactivating mutations of acetyltransferase genes in B-cell lymphoma.</strong> Nature 471: 189-195, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21390126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21390126</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21390126[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/nature09730" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21390126">Pasqualucci et al. (2011)</a> reported that the 2 most common types of B cell non-Hodgkin lymphoma (<a href="/entry/605027">605027</a>), follicular lymphoma and diffuse large B-cell lymphoma, harbor frequent structural alterations inactivating CREBBP and, more rarely, EP300 (<a href="/entry/602700">602700</a>), 2 highly related histone and nonhistone acetyltransferases (HATs) that act as transcriptional coactivators in multiple signaling pathways. Overall, about 39% of diffuse large B-cell lymphoma and 41% of follicular lymphoma cases display genomic deletions and/or somatic mutations that remove or inactivate the HAT coding domain of these 2 genes. These lesions usually affect 1 allele, suggesting that reduction in HAT dosage is important for lymphomagenesis. <a href="#41" class="mim-tip-reference" title="Pasqualucci, L., Dominguez-Sola, D., Chiarenza, A., Fabbri, G., Grunn, A., Trifonov, V., Kasper, L. H., Lerach, S., Tang, H., Ma, J., Rossi, D., Chadburn, A., Murty, V. V., Mullighan, C. G., Gaidano, G., Rabadan, R., Brindle, P. K., Dalla-Favera, R. <strong>Inactivating mutations of acetyltransferase genes in B-cell lymphoma.</strong> Nature 471: 189-195, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21390126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21390126</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21390126[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/nature09730" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21390126">Pasqualucci et al. (2011)</a> demonstrated specific defects in acetylation-mediated inactivation of the BCL6 oncoprotein (<a href="/entry/109565">109565</a>) and activation of the p53 tumor suppressor (<a href="/entry/191170">191170</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21390126" 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>Acute Myelogenous Leukemia</em></strong></p><p>
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<a href="#44" class="mim-tip-reference" title="Petrij, F., Giles, R. H., Dauwerse, H. G., Saris, J. J., Hennekam, R. C. M., Masuno, M., Tommerup, N., van Ommen, G.-J. B., Goodman, R. H., Peters, D. J. M., Breuning, M. H. <strong>Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP.</strong> Nature 376: 348-351, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7630403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7630403</a>] [<a href="https://doi.org/10.1038/376348a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7630403">Petrij et al. (1995)</a> noted a case of acute myeloid leukemia (<a href="/entry/601626">601626</a>) type M5b reported by <a href="#56" class="mim-tip-reference" title="Wessels, J. W., Mollevanger, P., Dauwerse, J. G., Cluitmans, F. H. M., Breuning, M. H., Beverstock, G. C. <strong>Two distinct loci on the short arm of chromosome 16 are involved in myeloid leukemia.</strong> Blood 77: 1555-1559, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2009371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2009371</a>]" pmid="2009371">Wessels et al. (1991)</a> that was associated with a translocation t(8;16) whose breakpoint was located in the same region as the breakpoints in Rubinstein-Taybi syndrome-1 (RSTS1; <a href="/entry/180849">180849</a>). <a href="#44" class="mim-tip-reference" title="Petrij, F., Giles, R. H., Dauwerse, H. G., Saris, J. J., Hennekam, R. C. M., Masuno, M., Tommerup, N., van Ommen, G.-J. B., Goodman, R. H., Peters, D. J. M., Breuning, M. H. <strong>Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP.</strong> Nature 376: 348-351, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7630403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7630403</a>] [<a href="https://doi.org/10.1038/376348a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7630403">Petrij et al. (1995)</a> proposed that the translocation may have joined CBP to an unknown gene on chromosome 8, leading to the malignancy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7630403+2009371" 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 positional cloning on chromosome 16, <a href="#8" class="mim-tip-reference" title="Borrow, J., Stanton, V. P., Jr., Andresen, J. M., Becher, R., Behm, F. G., Chaganti, R. S. K., Civin, C. I., Disteche, C., Dube, I., Frischauf, A. M., Horsman, D., Mitelman, F., Volinia, S., Watmore, A. E., Housman, D. E. <strong>The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein.</strong> Nature Genet. 14: 33-41, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782817</a>] [<a href="https://doi.org/10.1038/ng0996-33" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782817">Borrow et al. (1996)</a> implicated the CREB-binding protein in the M4/M5 subtype of acute myeloid leukemia. <a href="#8" class="mim-tip-reference" title="Borrow, J., Stanton, V. P., Jr., Andresen, J. M., Becher, R., Behm, F. G., Chaganti, R. S. K., Civin, C. I., Disteche, C., Dube, I., Frischauf, A. M., Horsman, D., Mitelman, F., Volinia, S., Watmore, A. E., Housman, D. E. <strong>The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein.</strong> Nature Genet. 14: 33-41, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782817</a>] [<a href="https://doi.org/10.1038/ng0996-33" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782817">Borrow et al. (1996)</a> also used positional cloning to identify a novel gene at the chromosome 8 breakpoint, which they termed MOZ (<a href="/entry/601408">601408</a>) for monocytic leukemia zinc finger protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8782817" 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="Sobulo, O. M., Borrow, J., Tomek, R., Reshmi, S., Harden, A., Schlegelberger, B., Housman, D., Doggett, N. A., Rowley, J. D., Zeleznik-Le, N. J. <strong>MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukemia with a t(11;16)(q23;p13.3).</strong> Proc. Nat. Acad. Sci. 94: 8732-8737, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9238046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9238046</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9238046[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.94.16.8732" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9238046">Sobulo et al. (1997)</a> stated that the recurring translocation t(11;16)(q23;p13.3) has been observed only in cases of acute leukemia or myelodysplasia secondary to therapy with drugs targeting DNA topoisomerase II (<a href="/entry/126430">126430</a>). <a href="#46" class="mim-tip-reference" title="Sobulo, O. M., Borrow, J., Tomek, R., Reshmi, S., Harden, A., Schlegelberger, B., Housman, D., Doggett, N. A., Rowley, J. D., Zeleznik-Le, N. J. <strong>MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukemia with a t(11;16)(q23;p13.3).</strong> Proc. Nat. Acad. Sci. 94: 8732-8737, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9238046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9238046</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9238046[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.94.16.8732" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9238046">Sobulo et al. (1997)</a> showed that in 2 patients the MLL gene was fused in-frame to a different exon of the CREBBP gene, producing chimeric proteins containing the AT-hooks, methyltransferase homology domain, and transcriptional repression domain of MLL fused to the CREB-binding domain or to the bromodomain of CREBBP. Both fusion products retained the histone acetyltransferase domain of CREBBP and may lead to leukemia by promoting histone acetylation of genomic regions targeted by the MLL AT-hooks, leading to transcriptional deregulation via aberrant chromatin organization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9238046" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#38" class="mim-tip-reference" title="Panagopoulos, I., Fioretos, T., Isaksson, M., Samuelsson, U., Billstrom, R., Strombeck, B., Mitelman, F., Johansson, B. <strong>Fusion of the MORF and CBP genes in acute myeloid leukemia with the t(10;16)(q22;p13).</strong> Hum. Molec. Genet. 10: 395-404, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11157802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11157802</a>] [<a href="https://doi.org/10.1093/hmg/10.4.395" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11157802">Panagopoulos et al. (2001)</a> reported a novel t(10;16)(q22;p13) chromosomal translocation in a childhood acute myelogenous leukemia (AML-M5a) leading to a MORF (<a href="/entry/605880">605880</a>)-CBP chimera. RT-PCR experiments yielded in-frame MORF-CBP and CBP-MORF fusion transcripts. Genomic analyses revealed that the breaks were close to Alu elements in intron 16 of MORF and intron 2 of CBP and that duplications had occurred near the breakpoints. The MORF-CBP protein retained the zinc fingers, 2 nuclear localization signals, the histone acetyltransferase (HAT) domain, a portion of the acidic domain of MORF, and the CBP protein downstream of codon 29. The part of CBP encoding the RARA-binding domain, the CREB-binding domain, the 3 cys/his-rich regions, the bromodomain, the HAT domain, and the glu-rich domains was present. In the reciprocal CBP-MORF, part of the acidic domain and the C-terminal ser- and met-rich regions of MORF may be driven by the CBP promoter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11157802" 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 t(8;16)(p11;p13) translocation, which is strongly associated with AML displaying monocytic differentiation, erythrophagocytosis by the leukemic cells, and a poor response to chemotherapy, fuses the CBP gene on chromosome 16p13 with the MOZ gene on chromosome 8p11. <a href="#39" class="mim-tip-reference" title="Panagopoulos, I., Isaksson, M., Lindvall, C., Hagemeijer, A., Mitelman, F., Johansson, B. <strong>Genomic characterization of MOZ/CBP and CBP/MOZ chimeras in acute myeloid leukemia suggests the involvement of a damage-repair mechanism in the origin of the t(8;16)(p11;p13).</strong> Genes Chromosomes Cancer 36: 90-98, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12461753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12461753</a>] [<a href="https://doi.org/10.1002/gcc.10137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12461753">Panagopoulos et al. (2003)</a> sequenced the breakpoints in 4 t(8;16)-positive AML cases. The breaks clustered in both CBP intron 2 and MOZ intron 16, and were close to repetitive elements; in 1 case, an Alu-Alu junction for the CBP/MOZ hybrid was identified. All 4 cases showed additional genomic events (i.e., deletions, duplications, and insertions) in the breakpoint regions in both the MOZ and CBP genes. Thus, the translocation did not originate through a simple end-to-end fusion. The findings of multiple breaks and rearrangements suggested the involvement of a damage repair mechanism in the origin of this translocation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12461753" 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>Acute Lymphoblastic Leukemia</em></strong></p><p>
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<a href="#33" class="mim-tip-reference" title="Mullighan, C. G., Zhang, J., Kasper, L. H., Lerach, S., Payne-Turner, D., Phillips, L. A., Heatley, S. L., Holmfeldt, L., Collins-Underwood, J. R., Ma, J., Buetow, K. H., Pui, C.-H., Baker, S. D., Brindle, P. K., Downing, J. R. <strong>CREBBP mutations in relapsed acute lymphoblastic leukaemia.</strong> Nature 471: 235-239, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21390130/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21390130</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21390130[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/nature09727" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21390130">Mullighan et al. (2011)</a> found that 18.3% of relapse cases of acute lymphoblastic leukemia had sequence or deletion mutations in CREBBP and that these frequently occurred in the histone acetyltransferase domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21390130" 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>While mapping and cloning the human CREBBP gene on 16p13.3, <a href="#18" class="mim-tip-reference" title="Giles, R. H., Petrij, F., Dauwerse, H. G., den Hollander, A. I., Lushnikova, T., van Ommen, G.-J. B., Goodman, R. H., Deaven, L. L., Doggett, N. A., Peters, D. J., Breuning, M. H. <strong>Construction of a 1.2-Mb contig surrounding, and molecular analysis of, the human CREB-binding protein (CBP/CREBBP) gene on chromosome 16p13.3.</strong> Genomics 42: 96-114, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9177780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9177780</a>] [<a href="https://doi.org/10.1006/geno.1997.4699" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9177780">Giles et al. (1997)</a> noticed an emerging pattern of relationship between this chromosome band and a region of chromosome 22q. CBP exhibits extensive homology to the adenovirus E1A-associated protein p300, whose gene (EP300; <a href="/entry/602700">602700</a>) maps to 22q13 (<a href="#15" class="mim-tip-reference" title="Eckner, R., Ewen, M. E., Newsome, D., Gerdes, M., DeCaprio, J. A., Lawrence, J. B., Livingston, D. M. <strong>Molecular cloning and functional analysis of the adenovirus E1A-associated 300-kD protein (p300) reveals a protein with properties of a transcriptional adaptor.</strong> Genes Dev. 8: 869-884, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7523245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7523245</a>] [<a href="https://doi.org/10.1101/gad.8.8.869" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7523245">Eckner et al., 1994</a>; <a href="#28" class="mim-tip-reference" title="Lundblad, J. R., Kwok, R. P. S., Laurance, M. E., Harter, M. L., Goodman, R. H. <strong>Adenoviral E1A-associated protein p300 as a functional homologue of the transcriptional co-activator CBP.</strong> Nature 374: 85-88, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7870179/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7870179</a>] [<a href="https://doi.org/10.1038/374085a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7870179">Lundblad et al., 1995</a>). They noted that the heme oxygenase-1 gene (HMOX1; <a href="/entry/141250">141250</a>) maps to 22q12 and the heme oxygenase-2 gene (HMOX2; <a href="/entry/141251">141251</a>) to 16p13.3 Furthermore, the gene for phosphomannomutase-2 (PMM2; <a href="/entry/601785">601785</a>) is on 16p13 and that for phosphomannomutase-1 (PMM1; <a href="/entry/601786">601786</a>) is on 22q13. Sequence comparison at the amino acid level revealed that homology between these paralogous proteins is high: 63% between CBP and p300, 66% between PMM1 and PMM2, and 74% between HMOX1 and HMOX2. By examination of genome databases, e.g., OMIM, <a href="#17" class="mim-tip-reference" title="Giles, R. H., Dauwerse, H. G., van Ommen, G.-J. B., Breuning, M. H. <strong>Do human chromosomal bands 16p13 and 22q11-13 share ancestral origins? (Letter)</strong> Am. J. Hum. Genet. 63: 1240-1242, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9758602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9758602</a>] [<a href="https://doi.org/10.1086/302044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9758602">Giles et al. (1998)</a> found 6 additional sets of paralogs mapping to 16p13 and 22q11-q13, although the extent of homology between these paralogous sets was not known. These pairs were SSTR5 (<a href="/entry/182455">182455</a>) and SSTR3 (<a href="/entry/182453">182453</a>) on 16 and 22, respectively; CSNK2A2 (<a href="/entry/115442">115442</a>) and CSNK1E (<a href="/entry/600863">600863</a>); UBE2I (<a href="/entry/601661">601661</a>) and UB2L3; MYH11 (<a href="/entry/160745">160745</a>) and MYH9 (<a href="/entry/160775">160775</a>); CRYM (<a href="/entry/123740">123740</a>) and a cluster of crystallin genes on chromosome 22, e.g., CRYBB1 (<a href="/entry/600929">600929</a>); IL4RA (<a href="/entry/147781">147781</a>) and IL2RB (<a href="/entry/146710">146710</a>). <a href="#17" class="mim-tip-reference" title="Giles, R. H., Dauwerse, H. G., van Ommen, G.-J. B., Breuning, M. H. <strong>Do human chromosomal bands 16p13 and 22q11-13 share ancestral origins? (Letter)</strong> Am. J. Hum. Genet. 63: 1240-1242, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9758602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9758602</a>] [<a href="https://doi.org/10.1086/302044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9758602">Giles et al. (1998)</a> postulated that these bands show homology because of an ancestral event of the type proposed by <a href="#36" class="mim-tip-reference" title="Ohno, S. <strong>Patterns in genome evolution.</strong> Curr. Opin. Genet. Dev. 3: 911-914, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8118217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8118217</a>] [<a href="https://doi.org/10.1016/0959-437x(93)90013-f" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8118217">Ohno (1993)</a>. Arguing from the fact that chromosome 14q carries SSTR1 (<a href="/entry/182451">182451</a>), UBE2L1 (<a href="/entry/600012">600012</a>), MYH6 (<a href="/entry/160710">160710</a>), and MYH7 (<a href="/entry/160760">160760</a>), whereas SSTR2 (<a href="/entry/182452">182452</a>), CSNK1D (<a href="/entry/600864">600864</a>), and CRYBA1 (<a href="/entry/123610">123610</a>) map to 17q, combined with the location on leukemia breakpoints, strongly suggested to <a href="#17" class="mim-tip-reference" title="Giles, R. H., Dauwerse, H. G., van Ommen, G.-J. B., Breuning, M. H. <strong>Do human chromosomal bands 16p13 and 22q11-13 share ancestral origins? (Letter)</strong> Am. J. Hum. Genet. 63: 1240-1242, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9758602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9758602</a>] [<a href="https://doi.org/10.1086/302044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9758602">Giles et al. (1998)</a> that these gene families arose by tetraploidization resulting in members on 14q, 16p, 17q, and 22q. Genetic redundancy is potentially of great relevance to organismal evolution since it may protect against potentially harmful mutations and may provide a pool of diverse yet functionally similar proteins for further evolution. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7870179+9177780+9758602+8118217+7523245" 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="#49" class="mim-tip-reference" title="Tanaka, Y., Naruse, I., Maekawa, T., Masuya, H., Shiroishi, T., Ishii, S. <strong>Abnormal skeletal patterning in embryos lacking a single Cbp allele: a partial similarity with Rubinstein-Taybi syndrome.</strong> Proc. Nat. Acad. Sci. 94: 10215-10220, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9294190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9294190</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9294190[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.94.19.10215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9294190">Tanaka et al. (1997)</a> generated Cbp +/- mice with haploinsufficiency of the Cbp protein, as demonstrated by Western blot analysis. Many of the mutant mice exhibited abnormal skeletal patterning similar to some features found in Rubinstein-Taybi syndrome, including delayed ossification of the frontal bones, enlarged anterior fontanels, and various anomalies of the sternum, rib cage, xiphoid process, and vertebrae. The mutant mice also had decreased levels of bone morphogenetic protein-7 (BMP7; <a href="/entry/112267">112267</a>), a molecule believed to be part of the signaling cascade in skeletal development. <a href="#49" class="mim-tip-reference" title="Tanaka, Y., Naruse, I., Maekawa, T., Masuya, H., Shiroishi, T., Ishii, S. <strong>Abnormal skeletal patterning in embryos lacking a single Cbp allele: a partial similarity with Rubinstein-Taybi syndrome.</strong> Proc. Nat. Acad. Sci. 94: 10215-10220, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9294190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9294190</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9294190[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.94.19.10215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9294190">Tanaka et al. (1997)</a> found that mice homozygous for the mutation died in utero. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9294190" 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="Kung, A. L., Rebel, V. I., Bronson, R. T., Ch'ng, L.-E., Sieff, C. A., Livingston, D. M., Yao, T.-P. <strong>Gene dose-dependent control of hematopoiesis and hematologic tumor suppression by CBP.</strong> Genes Dev. 14: 272-277, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10673499/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10673499</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10673499[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>]" pmid="10673499">Kung et al. (2000)</a> showed that Cbp +/- mice display an increased cancer risk similar to that seen in patients with RSTS. These results provided experimental evidence that CBP has tumor suppressing activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10673499" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To identify the physiologic functions of the Cbp protein using a loss-of-function mutant, <a href="#58" class="mim-tip-reference" title="Yamauchi, T., Oike, Y., Kamon, J., Waki, H., Komeda, K., Tsuchida, A., Date, Y., Li, M.-X., Miki, H., Akanuma, Y., Nagai, R., Kimura, S., Saheki, T., Nakazato, M., Naitoh, T., Yamamura, K., Kadowaki, T. <strong>Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygous mice.</strong> Nature Genet. 30: 221-226, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11818964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11818964</a>] [<a href="https://doi.org/10.1038/ng829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11818964">Yamauchi et al. (2002)</a> analyzed Cbp-deficient mice. As Crebbp-null mice died during embryogenesis, they used heterozygous mice. Unexpectedly, Crebbp +/- mice showed markedly reduced weight of white adipose tissue but not of other tissues. Despite this lipodystrophy, Crebbp +/- mice showed increased insulin sensitivity and glucose tolerance and were completely protected from body weight gain induced by high-fat diet. They observed increased leptin sensitivity and increased serum adiponectin (<a href="/entry/605441">605441</a>) levels in Crebbp +/- mice. These increased effects of insulin-sensitizing hormones secreted from white adipose tissue may explain, at least in part, the phenotypes of Crebbp +/- mice. The study demonstrated that CBP may function as a 'master-switch' between energy storage and expenditure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11818964" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Kasper, L. H., Boussouar, F., Ney, P. A., Jackson, C. W., Rehg, J., van Deursen, J. M., Brindle, P. K. <strong>A transcription-factor-binding surface of coactivator p300 is required for haematopoiesis.</strong> Nature 419: 738-743, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12384703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12384703</a>] [<a href="https://doi.org/10.1038/nature01062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12384703">Kasper et al. (2002)</a> demonstrated that the protein-binding KIX domains of CBP and p300 (<a href="/entry/602700">602700</a>) have nonredundant functions in mice. In mice homozygous for point mutations in the KIX domain of p300 designed to disrupt the binding surface for the transcription factors c-Myb (<a href="/entry/189990">189990</a>) and Creb, multilineage defects occur in hematopoiesis, including anemia, B-cell deficiency, thymic hypoplasia, megakaryocytosis, and thrombocytosis. By contrast, age-matched mice homozygous for identical mutations in the KIX domain of CBP are essentially normal. There is a synergistic genetic interaction between mutations in c-MYB and mutations in the KIX domain of p300, which suggests that the binding of c-MYB to this domain of p300 is crucial for the development and function of megakaryocytes. Thus, <a href="#22" class="mim-tip-reference" title="Kasper, L. H., Boussouar, F., Ney, P. A., Jackson, C. W., Rehg, J., van Deursen, J. M., Brindle, P. K. <strong>A transcription-factor-binding surface of coactivator p300 is required for haematopoiesis.</strong> Nature 419: 738-743, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12384703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12384703</a>] [<a href="https://doi.org/10.1038/nature01062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12384703">Kasper et al. (2002)</a> concluded that conserved domains in 2 highly related coactivators have contrasting roles in hematopoiesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12384703" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Bourtchouladze, R., Lidge, R., Catapano, R., Stanley, J., Gossweiler, S., Romashko, D., Scott, R., Tully, T. <strong>A mouse model of Rubinstein-Taybi syndrome: defective long-term memory is ameliorated by inhibitors of phosphodiesterase 4.</strong> Proc. Nat. Acad. Sci. 100: 10518-10522, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12930888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12930888</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12930888[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1834280100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12930888">Bourtchouladze et al. (2003)</a> reasoned that drugs that modulate CREB function by enhancing cAMP signaling might yield an effective treatment for the memory defect of CBP +/- mice. To this end, they designed a cell-based drug screen and discovered inhibitors of phosphodiesterase-4 (see <a href="/entry/600126">600126</a>, for example) to be particularly effective enhancers of CREB function. They extended previous behavioral observations by showing that CBP +/- mutants have impaired long-term memory but normal learning and short-term memory in an objective recognition task. They demonstrated that the prototypic PDE4 inhibitor, rolipram, and a novel one (HT0712) abolish the long-term memory defect of CBP +/- mice. The genetic lesion in CBP acts specifically to shift the dose sensitivity for HT0712 to enhance memory formation, which conveys molecular specificity on the drug's mechanism of action. The results suggested that PDE4 inhibitors might be used to treat the cognitive dysfunction of RSTS patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12930888" 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="Alarcon, J. M., Malleret, G., Touzani, K., Vronskaya, S., Ishii, S., Kandel, E. R., Barco, A. <strong>Chromatin acetylation, memory, and LTP are impaired in CBP+/- mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration.</strong> Neuron 42: 947-959, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15207239/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15207239</a>] [<a href="https://doi.org/10.1016/j.neuron.2004.05.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15207239">Alarcon et al. (2004)</a> found that transgenic mice haploinsufficient for the Cbp protein exhibited normal activity, motivation, anxiety, and working short-term memory, but had reduced long-term memory for fear and object recognition. Electrophysiologic measurements showed that the mutant mice had normal basal synaptic transmission, but had a defect in the late phase of hippocampal long-term potentiation that is dependent on transcriptional activation. Immunohistochemistry and Western blot analysis showed that the Cbp +/- mice had decreased acetylation of histone H2B (see <a href="/entry/609904">609904</a>), indicating an alteration in chromatin. Both enhancement of the expression of CREB-dependent genes and inhibition of histone deacetylation ameliorated the long-term potentiation and memory defects. <a href="#1" class="mim-tip-reference" title="Alarcon, J. M., Malleret, G., Touzani, K., Vronskaya, S., Ishii, S., Kandel, E. R., Barco, A. <strong>Chromatin acetylation, memory, and LTP are impaired in CBP+/- mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration.</strong> Neuron 42: 947-959, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15207239/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15207239</a>] [<a href="https://doi.org/10.1016/j.neuron.2004.05.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15207239">Alarcon et al. (2004)</a> concluded that some of the cognitive deficits in RTS may result from the continued requirement throughout life for both functions of CBP: activation of CREB and histone acetylation with chromatin remodeling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15207239" 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> rs121434624 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434624;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/rs121434624?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=rs121434624" 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=rs121434624" 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=RCV000010035" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010035" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010035</a>
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<p>In a patient with Rubinstein-Taybi syndrome-1 (RSTS1; <a href="/entry/180849">180849</a>), <a href="#44" class="mim-tip-reference" title="Petrij, F., Giles, R. H., Dauwerse, H. G., Saris, J. J., Hennekam, R. C. M., Masuno, M., Tommerup, N., van Ommen, G.-J. B., Goodman, R. H., Peters, D. J. M., Breuning, M. H. <strong>Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP.</strong> Nature 376: 348-351, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7630403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7630403</a>] [<a href="https://doi.org/10.1038/376348a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7630403">Petrij et al. (1995)</a> identified a C-T transition in the CREBBP gene, resulting in a stop codon and a truncated protein product. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7630403" 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>.0002 RUBINSTEIN-TAYBI SYNDROME 1</strong>
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CREBBP, GLN357TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121434625 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434625;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=rs121434625" 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=rs121434625" 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=RCV000010036" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010036" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010036</a>
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<p>In a patient with Rubinstein-Taybi syndrome-1 (RSTS1; <a href="/entry/180849">180849</a>), <a href="#44" class="mim-tip-reference" title="Petrij, F., Giles, R. H., Dauwerse, H. G., Saris, J. J., Hennekam, R. C. M., Masuno, M., Tommerup, N., van Ommen, G.-J. B., Goodman, R. H., Peters, D. J. M., Breuning, M. H. <strong>Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP.</strong> Nature 376: 348-351, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7630403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7630403</a>] [<a href="https://doi.org/10.1038/376348a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7630403">Petrij et al. (1995)</a> identified a C-T transition in the CREBBP gene, resulting in a stop codon and a truncated protein product. In this patient, the mutation destroyed a PvuII restriction site. Since the site was found to be intact in both chromosomes of the parents, the mutation in the patient must have been de novo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7630403" 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>.0003 RUBINSTEIN-TAYBI SYNDROME 1</strong>
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CREBBP, ARG1378PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121434626 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434626;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=rs121434626" 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=rs121434626" 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=RCV000010037" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010037" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010037</a>
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<p>In a patient with Rubinstein-Taybi syndrome-1 (<a href="/entry/180849">180849</a>), <a href="#34" class="mim-tip-reference" title="Murata, T., Kurokawa, R., Krones, A., Tatsumi, K., Ishii, M., Taki, T., Masuno, M., Ohashi, H., Yanagisawa, M., Rosenfeld, M. G., Glass, C. K., Hayashi, Y. <strong>Defect of histone acetyltransferase activity of the nuclear transcriptional coactivator CBP in Rubinstein-Taybi syndrome.</strong> Hum. Molec. Genet. 10: 1071-1076, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11331617/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11331617</a>] [<a href="https://doi.org/10.1093/hmg/10.10.1071" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11331617">Murata et al. (2001)</a> demonstrated a G-C transversion in the CREBBP gene, resulting in an arg1378-to-pro (R1378P) substitution. In a transgenic mouse model, this mutation abolished HAT activity of the CREB-binding protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11331617" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<span class="mim-font">
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<strong>.0004 RUBINSTEIN-TAYBI SYNDROME 1</strong>
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CREBBP, 2-BP DEL, NT5222
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2151330140 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2151330140;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=rs2151330140" 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=rs2151330140" 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=RCV000010038" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010038" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010038</a>
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<p>In a patient with Rubinstein-Taybi syndrome-1 (<a href="/entry/180849">180849</a>), <a href="#34" class="mim-tip-reference" title="Murata, T., Kurokawa, R., Krones, A., Tatsumi, K., Ishii, M., Taki, T., Masuno, M., Ohashi, H., Yanagisawa, M., Rosenfeld, M. G., Glass, C. K., Hayashi, Y. <strong>Defect of histone acetyltransferase activity of the nuclear transcriptional coactivator CBP in Rubinstein-Taybi syndrome.</strong> Hum. Molec. Genet. 10: 1071-1076, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11331617/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11331617</a>] [<a href="https://doi.org/10.1093/hmg/10.10.1071" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11331617">Murata et al. (2001)</a> demonstrated a 2-bp deletion in the CREBBP gene of nucleotides 5222-5223, leading to missense translation from codons 1469-1476, followed by premature termination at codon 1477. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11331617" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 RUBINSTEIN-TAYBI SYNDROME 1, INCOMPLETE</strong>
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CREBBP, TYR1175CYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28937315 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28937315;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=rs28937315" 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=rs28937315" 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=RCV000010039 OR RCV004609293" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010039, RCV004609293" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010039...</a>
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<p>In a patient with a mild form of Rubinstein-Taybi syndrome-1 (<a href="/entry/180849">180849</a>), <a href="#5" class="mim-tip-reference" title="Bartsch, O., Locher, K., Meinecke, P., Kress, W., Seemanova, E., Wagner, A., Ostermann, K., Rodel, G. <strong>Molecular studies in 10 cases of Rubinstein-Taybi syndrome, including a mild variant showing a missense mutation in codon 1175 of CREBBP.</strong> J. Med. Genet. 39: 496-501, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12114483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12114483</a>] [<a href="https://doi.org/10.1136/jmg.39.7.496" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12114483">Bartsch et al. (2002)</a> identified a 3524A-G transition in the CREBBP gene, resulting in a tyr1175-to-cys (Y1175C) substitution. The authors concluded that the missense mutation resulted in the milder phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12114483" 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="0006" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0006 RUBINSTEIN-TAYBI SYNDROME 1</strong>
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CREBBP, GLU1278LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267606752 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606752;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=rs267606752" 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=rs267606752" 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=RCV000010040 OR RCV000255660 OR RCV001260694 OR RCV001267080 OR RCV001813970 OR RCV002496320 OR RCV004742224" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010040, RCV000255660, RCV001260694, RCV001267080, RCV001813970, RCV002496320, RCV004742224" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010040...</a>
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<span class="mim-text-font">
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<p>In a patient with Rubinstein-Taybi syndrome-1 (<a href="/entry/180849">180849</a>), <a href="#21" class="mim-tip-reference" title="Kalkhoven, E., Roelfsema, J. H., Teunissen, H., den Boer, A., Ariyurek, Y., Zantema, A., Breuning, M. H., Hennekam, R. C. M., Peters, D. J. M. <strong>Loss of CBP acetyltransferase activity by PHD finger mutations in Rubinstein-Taybi syndrome.</strong> Hum. Molec. Genet. 12: 441-450, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12566391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12566391</a>] [<a href="https://doi.org/10.1093/hmg/ddg039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12566391">Kalkhoven et al. (2003)</a> identified a 3832G-A transition in the CREBBP gene, resulting in a glu1278-to-lys (E1278K) substitution at a conserved residue within the PHD finger of the HAT domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12566391" 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">rs1567277287 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1567277287;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=rs1567277287" 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=rs1567277287" 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=RCV000010041" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010041" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010041</a>
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<p>In a patient with Rubinstein-Taybi syndrome-1 (<a href="/entry/180849">180849</a>), <a href="#21" class="mim-tip-reference" title="Kalkhoven, E., Roelfsema, J. H., Teunissen, H., den Boer, A., Ariyurek, Y., Zantema, A., Breuning, M. H., Hennekam, R. C. M., Peters, D. J. M. <strong>Loss of CBP acetyltransferase activity by PHD finger mutations in Rubinstein-Taybi syndrome.</strong> Hum. Molec. Genet. 12: 441-450, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12566391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12566391</a>] [<a href="https://doi.org/10.1093/hmg/ddg039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12566391">Kalkhoven et al. (2003)</a> identified an A-to-T transversion 2 bp 5-prime to exon 22 in the CREBBP gene. The mutation was predicted to result in aberrant splicing and loss of the 26 amino acids encoded by exon 22. These residues lie in the middle of the PHD finger of the HAT domain. Expression studies revealed loss of HAT activity in transiently transfected cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12566391" 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>.0008 RUBINSTEIN-TAYBI SYNDROME 1, INCOMPLETE</strong>
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CREBBP, THR910ALA
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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> rs143247685 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs143247685;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/rs143247685?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=rs143247685" 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=rs143247685" 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=RCV000022942 OR RCV000145728 OR RCV000421582 OR RCV001087789 OR RCV001252206 OR RCV002224958 OR RCV002311524 OR RCV003974853" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022942, RCV000145728, RCV000421582, RCV001087789, RCV001252206, RCV002224958, RCV002311524, RCV003974853" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022942...</a>
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<p>In a girl, her mother, and maternal grandmother with an incomplete form of Rubinstein-Taybi syndrome-1 (<a href="/entry/180849">180849</a>), <a href="#4" class="mim-tip-reference" title="Bartsch, O., Kress, W., Kempf, O., Lechno, S., Haaf, T., Zechner, U. <strong>Inheritance and variable expression in Rubinstein-Taybi syndrome.</strong> Am. J. Med. Genet. 152A: 2254-2261, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20684013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20684013</a>] [<a href="https://doi.org/10.1002/ajmg.a.33598" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20684013">Bartsch et al. (2010)</a> identified a heterozygous 2728A-G transition in exon 14 of the CREBBP gene, resulting in a thr910-to-ala (T910A) substitution in a partially conserved residue. The mutation occurred outside the crucial histone acetyltransferase domain, which could explain the milder phenotype. The 12-year-old female proband had mild dysmorphic features, such as high-arched eyebrows, elongated face, prominent nose, high-arched palate, short broad thumbs, and broad halluces. She had a short attention span, dyslexia, dyscalculia, reading difficulties, and needed special teaching in language and mathematics. Her mother had similar facial features, was mildly obese, and had normal intelligence. The grandmother reportedly had a similar appearance and had not finished school. The report confirmed autosomal dominant inheritance of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20684013" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 MENKE-HENNEKAM SYNDROME 1</strong>
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CREBBP, CYS1710ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1567265203 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1567265203;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=rs1567265203" 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=rs1567265203" 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=RCV000757965" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000757965" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000757965</a>
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<p>In a boy (patient 1) with Menke-Hennekam syndrome-1 (MKHK1; <a href="/entry/618332">618332</a>), <a href="#32" class="mim-tip-reference" title="Menke, L. A., van Belzen, M. J., Alders, M., Cristofoli, F., DDD Study, Ehmke, N., Fergelot, P., Foster, A., Gerkes, E. H., Hoffer, M. J. V., Horn, D., Kant, S. G., and 12 others. <strong>CREBBP mutations in individuals without Rubinstein-Taybi syndrome phenotype.</strong> Am. J. Med. Genet. 170A: 2681-2693, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27311832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27311832</a>] [<a href="https://doi.org/10.1002/ajmg.a.37800" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27311832">Menke et al. (2016)</a> detected a heterozygous T-to-C transition at nucleotide 5128 (c.5128T-C, GRCh37) in exon 30 of the CREBBP gene resulting in a cys-to-arg substitution at codon 1710 (C1710R) in the ZNF2 domain of the protein. This de novo mutation was not present in the ESP or ExAC databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27311832" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 MENKE-HENNEKAM SYNDROME 1</strong>
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CREBBP, ARG1867GLN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1131691326 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1131691326;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=rs1131691326" 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=rs1131691326" 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=RCV000493961 OR RCV000757966 OR RCV003758800" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000493961, RCV000757966, RCV003758800" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000493961...</a>
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<p>In a girl (patient 8) with Menke-Hennekam syndrome-1 (MKHK1; <a href="/entry/618332">618332</a>), <a href="#32" class="mim-tip-reference" title="Menke, L. A., van Belzen, M. J., Alders, M., Cristofoli, F., DDD Study, Ehmke, N., Fergelot, P., Foster, A., Gerkes, E. H., Hoffer, M. J. V., Horn, D., Kant, S. G., and 12 others. <strong>CREBBP mutations in individuals without Rubinstein-Taybi syndrome phenotype.</strong> Am. J. Med. Genet. 170A: 2681-2693, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27311832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27311832</a>] [<a href="https://doi.org/10.1002/ajmg.a.37800" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27311832">Menke et al. (2016)</a> detected a heterozygous G-to-A transition at nucleotide 5600 (c.5600G-A, GRCh37) in exon 31 of the CREBBP gene resulting in an arg-to-gln substitution at codon 1867 (R1867Q). The patient had a dizygotic twin brother with mild developmental delay. The mutation was shown to have occurred de novo and was not present in the ESP or ExAC databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27311832" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Menke, L. A., DDD Study, Gardeitchik, T., Hammond, P., Heimdal, K. R., Houge, G., Hufnagel, S. B., Ji, J., Johansson, S., Kant, S. G., Kinning, E., Leon, E. L., and 14 others. <strong>Further delineation of an entity caused by CREBBP and EP300 mutations but not resembling Rubinstein-Taybi syndrome.</strong> Am. J. Med. Genet. 176: 862-876, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29460469/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29460469</a>] [<a href="https://doi.org/10.1002/ajmg.a.38626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29460469">Menke et al. (2018)</a> detected the R1867Q mutation (c.5600G-A, NM_004380.2) in a 57-year-old man from the Netherlands (patient C16). Inheritance of the mutation could not be determined because the patient's parents were deceased. The mutation was not present in gnomAD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29460469" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 MENKE-HENNEKAM SYNDROME 1</strong>
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CREBBP, ARG1868TRP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs886039491 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886039491;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=rs886039491" 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=rs886039491" 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=RCV000254930 OR RCV000757967 OR RCV002282094 OR RCV003156089" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000254930, RCV000757967, RCV002282094, RCV003156089" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000254930...</a>
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<p>In 2 unrelated girls (patients 9 and 10) with Menke-Hennekam syndrome-1 (MKHK1; <a href="/entry/618332">618332</a>), <a href="#32" class="mim-tip-reference" title="Menke, L. A., van Belzen, M. J., Alders, M., Cristofoli, F., DDD Study, Ehmke, N., Fergelot, P., Foster, A., Gerkes, E. H., Hoffer, M. J. V., Horn, D., Kant, S. G., and 12 others. <strong>CREBBP mutations in individuals without Rubinstein-Taybi syndrome phenotype.</strong> Am. J. Med. Genet. 170A: 2681-2693, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27311832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27311832</a>] [<a href="https://doi.org/10.1002/ajmg.a.37800" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27311832">Menke et al. (2016)</a> detected heterozygosity for a C-to-T transition at nucleotide 5602 (c.5602C-T, GRCh37) in exon 31 of the CREBBP gene, resulting in an atg1868-to-trp (R1868W) substitution. This de novo mutation was not present in the ESP or ExAC databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27311832" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Menke, L. A., DDD Study, Gardeitchik, T., Hammond, P., Heimdal, K. R., Houge, G., Hufnagel, S. B., Ji, J., Johansson, S., Kant, S. G., Kinning, E., Leon, E. L., and 14 others. <strong>Further delineation of an entity caused by CREBBP and EP300 mutations but not resembling Rubinstein-Taybi syndrome.</strong> Am. J. Med. Genet. 176: 862-876, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29460469/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29460469</a>] [<a href="https://doi.org/10.1002/ajmg.a.38626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29460469">Menke et al. (2018)</a> found the R1868W mutation (c.5602C-T, NM_004380.2) in 3 unrelated children (patients C17, C18, and C19) with MKHK1. The mutation occurred de novo in all 3 cases and was not found in gnomAD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29460469" 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>.0012 MENKE-HENNEKAM SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs797045037 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797045037;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=rs797045037" 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=rs797045037" 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=RCV000191076 OR RCV000523539 OR RCV000757968 OR RCV001260745 OR RCV002517032 OR RCV003422092 OR RCV003458352" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000191076, RCV000523539, RCV000757968, RCV001260745, RCV002517032, RCV003422092, RCV003458352" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000191076...</a>
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<p>In a girl (patient 11) with Menke-Hennekam syndrome-1 (MKHK1; <a href="/entry/618332">618332</a>), <a href="#32" class="mim-tip-reference" title="Menke, L. A., van Belzen, M. J., Alders, M., Cristofoli, F., DDD Study, Ehmke, N., Fergelot, P., Foster, A., Gerkes, E. H., Hoffer, M. J. V., Horn, D., Kant, S. G., and 12 others. <strong>CREBBP mutations in individuals without Rubinstein-Taybi syndrome phenotype.</strong> Am. J. Med. Genet. 170A: 2681-2693, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27311832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27311832</a>] [<a href="https://doi.org/10.1002/ajmg.a.37800" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27311832">Menke et al. (2016)</a> identified a heterozygous c.5614A-G transition (c.5614A-G, GRCh37) in exon 31 of the CREBBP gene that resulted in a met1872-to-val substitution (M1872V). The mutation occurred de novo and was not found in the ESP or ExAC databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27311832" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Menke, L. A., DDD Study, Gardeitchik, T., Hammond, P., Heimdal, K. R., Houge, G., Hufnagel, S. B., Ji, J., Johansson, S., Kant, S. G., Kinning, E., Leon, E. L., and 14 others. <strong>Further delineation of an entity caused by CREBBP and EP300 mutations but not resembling Rubinstein-Taybi syndrome.</strong> Am. J. Med. Genet. 176: 862-876, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29460469/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29460469</a>] [<a href="https://doi.org/10.1002/ajmg.a.38626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29460469">Menke et al. (2018)</a> identified the M1872V mutation (c.5614A-G, NM_004380.2) in a 9-year-old Norwegian boy. The mutation was shown to have occurred de novo and was not present in gnomAD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29460469" 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 MENKE-HENNEKAM SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1567265131 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1567265131;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=rs1567265131" 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=rs1567265131" 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=RCV000757969 OR RCV003317356" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000757969, RCV003317356" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000757969...</a>
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<p>In a 17-year-old Sardinian boy with Menke-Hennekam syndrome-1 (MKHK1; <a href="/entry/618332">618332</a>), <a href="#2" class="mim-tip-reference" title="Angius, A., Uva, P., Oppo, M., Persico, I., Onano, S., Olla, S., Pes, V., Perria, C., Cuccuru, G., Atzeni, R., Serra, G., Cucca, F., Sotgiu, S., Hennekam, R. C., Crisponi, L. <strong>Confirmation of a new phenotype in an individual with a variant in the last part of exon 30 of CREBBP.</strong> Am. J. Med. Genet. 179A: 634-638, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30737887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30737887</a>] [<a href="https://doi.org/10.1002/ajmg.a.61052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30737887">Angius et al. (2019)</a> found a heterozygous c.5170G-A transition (c.5170G-A, NM_004380) in exon 30 of the CREBBP gene that resulted in a glu1724-to-lys (E1724K) substitution in the ZNF2 domain of the protein. The patient mild intellectual disability and dysmorphisms as well as obesity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30737887" 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="Alarcon2004" class="mim-anchor"></a>
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Alarcon, J. M., Malleret, G., Touzani, K., Vronskaya, S., Ishii, S., Kandel, E. R., Barco, A.
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<strong>Chromatin acetylation, memory, and LTP are impaired in CBP+/- mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration.</strong>
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Neuron 42: 947-959, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15207239/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15207239</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15207239" 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/j.neuron.2004.05.021" target="_blank">Full Text</a>]
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Angius, A., Uva, P., Oppo, M., Persico, I., Onano, S., Olla, S., Pes, V., Perria, C., Cuccuru, G., Atzeni, R., Serra, G., Cucca, F., Sotgiu, S., Hennekam, R. C., Crisponi, L.
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<strong>Confirmation of a new phenotype in an individual with a variant in the last part of exon 30 of CREBBP.</strong>
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Am. J. Med. Genet. 179A: 634-638, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30737887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30737887</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30737887" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.61052" target="_blank">Full Text</a>]
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Arias, J., Alberts, A. S., Brindle, P., Claret, F. X., Smeal, T., Karin, M., Feramisco, J., Montminy, M.
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<strong>Activation of cAMP and mitogen responsive genes relies on a common nuclear factor.</strong>
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Nature 370: 226-229, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8028671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8028671</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8028671" 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/10.1038/370226a0" target="_blank">Full Text</a>]
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Bartsch, O., Kress, W., Kempf, O., Lechno, S., Haaf, T., Zechner, U.
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<strong>Inheritance and variable expression in Rubinstein-Taybi syndrome.</strong>
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Am. J. Med. Genet. 152A: 2254-2261, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20684013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20684013</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20684013" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.33598" target="_blank">Full Text</a>]
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Bartsch, O., Locher, K., Meinecke, P., Kress, W., Seemanova, E., Wagner, A., Ostermann, K., Rodel, G.
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<strong>Molecular studies in 10 cases of Rubinstein-Taybi syndrome, including a mild variant showing a missense mutation in codon 1175 of CREBBP.</strong>
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J. Med. Genet. 39: 496-501, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12114483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12114483</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12114483" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.39.7.496" target="_blank">Full Text</a>]
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Blobel, G. A., Nakajima, T., Eckner, R., Montminy, M., Orkin, S. H.
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<strong>CREB-binding protein cooperates with transcription factor GATA-1 and is required for erythroid differentiation.</strong>
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Proc. Nat. Acad. Sci. 95: 2061-2066, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9482838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9482838</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9482838[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=9482838" 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.95.5.2061" target="_blank">Full Text</a>]
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Blough, R. I., Petrij, F., Dauwerse, J. G., Milatovich-Cherry, A., Weiss, L., Saal, H. M., Rubinstein, J. H.
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<strong>Variation in microdeletions of the cyclic AMP-responsive element-binding protein gene at chromosome band 16p13.3 in the Rubinstein-Taybi syndrome.</strong>
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<div class="">
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<p class="mim-text-font">
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Weaver, B. K., Kumar, K. P., Reich, N. C.
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<strong>Interferon regulatory factor 3 and CREB-binding protein/p300 are subunits of double-stranded RNA-activated transcription factor DRAF1.</strong>
|
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Molec. Cell. Biol. 18: 1359-1368, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9488451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9488451</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9488451[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=9488451" 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.18.3.1359" target="_blank">Full Text</a>]
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<li>
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<a id="56" class="mim-anchor"></a>
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<a id="Wessels1991" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wessels, J. W., Mollevanger, P., Dauwerse, J. G., Cluitmans, F. H. M., Breuning, M. H., Beverstock, G. C.
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<strong>Two distinct loci on the short arm of chromosome 16 are involved in myeloid leukemia.</strong>
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Blood 77: 1555-1559, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2009371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2009371</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2009371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="57" class="mim-anchor"></a>
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<a id="Wydner1995" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wydner, K. L., Bhattacharya, S., Eckner, R., Lawrence, J. B., Livingston, D. M.
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<strong>Localization of human CREB-binding protein gene (CREBBP) to 16p13.2-p13.3 by fluorescence in situ hybridization.</strong>
|
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Genomics 30: 395-396, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8586450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8586450</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8586450" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="58" class="mim-anchor"></a>
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<a id="Yamauchi2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yamauchi, T., Oike, Y., Kamon, J., Waki, H., Komeda, K., Tsuchida, A., Date, Y., Li, M.-X., Miki, H., Akanuma, Y., Nagai, R., Kimura, S., Saheki, T., Nakazato, M., Naitoh, T., Yamamura, K., Kadowaki, T.
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<strong>Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygous mice.</strong>
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Nature Genet. 30: 221-226, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11818964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11818964</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11818964" 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/ng829" target="_blank">Full Text</a>]
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<li>
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<a id="59" class="mim-anchor"></a>
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<a id="Zanger2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zanger, K., Radovick, S., Wondisford, F. E.
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<strong>CREB binding protein recruitment to the transcription complex requires growth factor-dependent phosphorylation of its GF box.</strong>
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Molec. Cell 7: 551-558, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11463380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11463380</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11463380" 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/s1097-2765(01)00202-7" target="_blank">Full Text</a>]
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<a id="Zhong2002" class="mim-anchor"></a>
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<p class="mim-text-font">
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Zhong, H., May, M. J., Jimi, E., Ghosh, S.
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<strong>The phosphorylation status of nuclear NF-kappa-B determines its association with CBP/p300 or HDAC-1.</strong>
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Molec. Cell 9: 625-636, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11931769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11931769</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11931769" 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/s1097-2765(02)00477-x" target="_blank">Full Text</a>]
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<a id="61" class="mim-anchor"></a>
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<a id="Zhou2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhou, X. Y., Shibusawa, N., Naik, K., Porras, D., Temple, K., Ou, H., Kaihara, K., Roe, M. W., Brady, M. J., Wondisford, F. E.
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<strong>Insulin regulation of hepatic gluconeogenesis through phosphorylation of CREB-binding protein.</strong>
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Nature Med. 10: 633-637, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15146178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15146178</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15146178" 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/nm1050" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Matthew B. Gross - updated : 01/14/2025
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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">
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Ada Hamosh - updated : 02/22/2019<br>Ada Hamosh - updated : 01/08/2015<br>Cassandra L. Kniffin - updated : 6/20/2011<br>Ada Hamosh - updated : 6/14/2011<br>Cassandra L. Kniffin - updated : 6/21/2010<br>Patricia A. Hartz - updated : 12/8/2009<br>Ada Hamosh - updated : 9/9/2009<br>Ada Hamosh - updated : 6/4/2009<br>Ada Hamosh - updated : 8/29/2008<br>Ada Hamosh - updated : 3/7/2008<br>Marla J. F. O'Neill - updated : 12/21/2007<br>Cassandra L. Kniffin - updated : 8/13/2007<br>Ada Hamosh - updated : 1/30/2006<br>Cassandra L. Kniffin - updated : 5/4/2005<br>George E. Tiller - updated : 1/6/2005<br>George E. Tiller - updated : 10/26/2004<br>Marla J. F. O'Neill - updated : 5/19/2004<br>Cassandra L. Kniffin - reorganized : 11/19/2003<br>Victor A. McKusick - updated : 10/10/2003<br>Patricia A. Hartz - updated : 3/11/2003<br>Victor A. McKusick - updated : 2/11/2003<br>Ada Hamosh - updated : 11/12/2002<br>Stylianos E. Antonarakis - updated : 9/23/2002<br>Ada Hamosh - updated : 2/7/2002<br>Victor A. McKusick - updated : 1/22/2002<br>Stylianos E. Antonarakis - updated : 11/5/2001<br>George E. Tiller - updated : 10/10/2001<br>George E. Tiller - updated : 4/24/2001<br>Stylianos E. Antonarakis - updated : 4/16/2001<br>George E. Tiller - updated : 11/17/2000<br>Michael J. Wright - updated : 8/10/2000<br>Paul J. Converse - updated : 7/7/2000<br>Victor A. McKusick - updated : 4/25/2000<br>Victor A. McKusick - updated : 1/13/2000<br>Patti M. Sherman - updated : 4/16/1999<br>Ada Hamosh - updated : 3/25/1999<br>Victor A. McKusick - updated : 10/23/1998<br>Victor A. McKusick - updated : 8/17/1998<br>Stylianos E. Antonarakis - updated : 1/23/1998<br>Ethylin Wang Jabs - updated : 11/18/1997<br>Victor A. McKusick - updated : 9/10/1997<br>Mark H. Paalman - updated : 8/31/1996
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</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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Victor A. McKusick : 10/6/1994
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</span>
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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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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 01/14/2025
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</span>
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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 : 01/14/2025<br>alopez : 05/26/2023<br>carol : 07/08/2019<br>alopez : 07/01/2019<br>alopez : 02/22/2019<br>carol : 02/06/2017<br>alopez : 01/08/2015<br>alopez : 12/22/2014<br>mgross : 1/29/2013<br>wwang : 7/1/2011<br>ckniffin : 6/20/2011<br>alopez : 6/16/2011<br>terry : 6/14/2011<br>carol : 5/25/2011<br>wwang : 1/24/2011<br>ckniffin : 1/6/2011<br>wwang : 6/28/2010<br>ckniffin : 6/21/2010<br>carol : 4/5/2010<br>mgross : 1/4/2010<br>terry : 12/8/2009<br>carol : 9/15/2009<br>terry : 9/9/2009<br>alopez : 6/4/2009<br>terry : 2/2/2009<br>alopez : 9/11/2008<br>terry : 8/29/2008<br>wwang : 4/23/2008<br>alopez : 3/20/2008<br>alopez : 3/20/2008<br>terry : 3/7/2008<br>wwang : 12/26/2007<br>terry : 12/21/2007<br>wwang : 8/23/2007<br>ckniffin : 8/13/2007<br>alopez : 2/1/2006<br>terry : 1/30/2006<br>alopez : 9/27/2005<br>tkritzer : 5/13/2005<br>ckniffin : 5/4/2005<br>alopez : 1/6/2005<br>tkritzer : 10/26/2004<br>alopez : 6/28/2004<br>carol : 5/19/2004<br>ckniffin : 11/24/2003<br>carol : 11/19/2003<br>ckniffin : 11/13/2003<br>tkritzer : 11/6/2003<br>ckniffin : 11/3/2003<br>cwells : 10/10/2003<br>mgross : 3/14/2003<br>terry : 3/11/2003<br>tkritzer : 2/11/2003<br>alopez : 11/13/2002<br>terry : 11/12/2002<br>mgross : 9/23/2002<br>mgross : 9/23/2002<br>mgross : 9/23/2002<br>alopez : 2/7/2002<br>terry : 2/7/2002<br>alopez : 1/30/2002<br>terry : 1/22/2002<br>mgross : 11/5/2001<br>alopez : 10/15/2001<br>cwells : 10/15/2001<br>cwells : 10/10/2001<br>cwells : 5/2/2001<br>cwells : 4/24/2001<br>mgross : 4/16/2001<br>terry : 11/17/2000<br>alopez : 8/10/2000<br>mgross : 7/7/2000<br>mcapotos : 5/24/2000<br>mcapotos : 5/22/2000<br>terry : 4/25/2000<br>mgross : 1/18/2000<br>terry : 1/13/2000<br>psherman : 4/20/1999<br>psherman : 4/20/1999<br>psherman : 4/16/1999<br>mgross : 3/25/1999<br>dkim : 11/6/1998<br>terry : 10/27/1998<br>terry : 10/27/1998<br>terry : 10/27/1998<br>terry : 10/23/1998<br>carol : 8/18/1998<br>terry : 8/17/1998<br>terry : 6/4/1998<br>carol : 1/26/1998<br>carol : 1/23/1998<br>mark : 11/19/1997<br>jenny : 11/18/1997<br>jenny : 11/18/1997<br>jenny : 11/18/1997<br>terry : 9/12/1997<br>terry : 9/10/1997<br>mark : 9/10/1996<br>mark : 9/3/1996<br>mark : 8/31/1996<br>mark : 1/14/1996<br>terry : 11/16/1995<br>mark : 8/18/1995<br>carol : 3/2/1995<br>carol : 3/1/1995<br>carol : 10/7/1994<br>carol : 10/6/1994
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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 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">
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<strong>*</strong> 600140
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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CREB-BINDING PROTEIN; CREBBP
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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CBP
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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>
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<span class="mim-font">
|
|
Other entities represented in this entry:
|
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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CBP/MOZ FUSION GENE, INCLUDED
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</span>
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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>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: CREBBP</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
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Cytogenetic location: 16p13.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 16:3,725,054-3,880,713 </span>
|
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</em>
|
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</strong>
|
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<span class="small">(from NCBI)</span>
|
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
|
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Phenotype
|
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</th>
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<th>
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Phenotype <br /> MIM number
|
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</th>
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<th>
|
|
Inheritance
|
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</th>
|
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
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</tr>
|
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</thead>
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<td rowspan="2">
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<span class="mim-font">
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16p13.3
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<td>
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<span class="mim-font">
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Menke-Hennekam syndrome 1
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</td>
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<td>
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<span class="mim-font">
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618332
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<span class="mim-font">
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Autosomal dominant
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</td>
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<span class="mim-font">
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3
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<span class="mim-font">
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Rubinstein-Taybi syndrome 1
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</td>
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<td>
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<span class="mim-font">
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180849
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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<td>
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<span class="mim-font">
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3
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</table>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</h4>
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<span class="mim-text-font">
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<p>When cellular levels of cAMP increase, a cascade of events leads to the induction of genes that contain cis-regulatory elements called cAMP-response elements (CREs). Elevated cAMP levels cause stimulation and nuclear translocation of protein kinase A (PKA; see 176911), which activates the transcription factor CREB (CRE-binding protein; see 123810) by phosphorylating it at a single residue, serine-133 (Gonzalez and Montminy, 1989). </p><p>Chrivia et al. (1993) reported the discovery of a nuclear transcriptional coactivator protein, CREB-binding protein (CBP), that binds specifically to the PKA-phosphorylated form of the CREB protein. CBP is a large protein with a molecular mass of about 250 kD which contains a bromodomain, i.e., a conserved structural unit important for protein-protein interactions. In Drosophila and yeast, this domain is found in coactivator proteins involved in signal-dependent, but not basal, transcription (Nordheim, 1994). </p><p>To isolate the gene responsible for Rubinstein-Taybi syndrome (RSTS1; 180849), which is associated with breakpoints in and microdeletions of chromosome 16p13.3, Petrij et al. (1995) used FISH to situate all RSTS breakpoints in an area of 150 kb, thus defining a candidate region. Complementary DNAs from this area showed very high sequence homology with mouse CBP. Further studies indicated that the human CBP gene spans at least the 150-kb genomic area containing the RSTS breakpoints. Giles et al. (1997) reported the cloning and sequencing of human CREBBP, which encodes a deduced 2,442-amino acid protein with a molecular mass of 265 kD with 95% homology to the mouse protein. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p><strong><em>Crystal Structure</em></strong></p><p>
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Liu et al. (2008) described a high resolution x-ray crystal structure of a semisynthetic heterodimeric p300 (602700) HAT domain in complex with a bisubstrate inhibitor, Lys-CoA. This structure showed that p300/CBP is a distant cousin of other structurally characterized HATs, but revealed several novel features that explain the broad substrate specificity and preference for nearby basic residues. Based on this structure and accompanying biochemical data, Liu et al. (2008) proposed that p300/CBP uses an unusual hit-and-run (Theorell-Chance) catalytic mechanism that is distinct from other characterized HATs. Several disease-associated mutations could also be readily accounted for by the p300 HAT structure. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Petrij et al. (1995) used FISH to show that mouse CBP hybridized to human 16p13.3. Chen and Korenberg (1995) also mapped CREBBP to 16p13.3 using a cDNA probe for the mouse gene in fluorescence in situ hybridization. Using a human genomic clone for FISH, Wydner et al. (1995) mapped CREBBP to 16p13.3-p13.2. </p>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Kwok et al. (1994) used fluorescence anisotropy measurements to define the equilibrium binding parameters of the phosphoCREB:CBP interaction and reported that CBP can activate transcription through a region in its C terminus. The activation domain of CBP interacts directly with the basal transcription factor TFIIB (189963). As TFIIB interacts with the TATA-box-binding protein TBP1 (186852), a continuous chain of physical contacts is established linking the stimulus-activated phosphoCREB, bound distal to the promoter, with the polymerase II complex that initiates transcription (Nordheim, 1994). Acting as a coactivator, CBP augments the activity of phosphorylated CREB to activate transcription of cAMP-responsive genes. </p><p>Arias et al. (1994) microinjected an anti-CBP antiserum into fibroblasts and determined that transcription from a cAMP promoter can be inhibited. Arias et al. (1994) also reported that CBP cooperates with upstream activators, such as JUN (165160), that are involved in mitogen-responsive transcription. Studies indicated that when JUN was phosphorylated at the transcriptionally stimulatory sites ser73 and ser63, it bound CBP with comparable affinity to CREB. They proposed that CBP is recruited to the promoter through interaction with certain phosphorylated factors and that CBP may thus play a critical role in the transmission of inductive signals from cell surface receptors to the transcriptional apparatus. </p><p>Sterol regulatory element-binding proteins (SREBPs; e.g., 184756) activate transcription of genes whose products are involved in the cellular uptake and synthesis of cholesterol. Oliner et al. (1996) showed that the putative activation domain of SREBP binds specifically to the N-terminal domains of recombinant CBP and p300 (EP300; 602700), a CREBBP-related protein. Transfection studies demonstrated that CBP enhances the ability of SREBP to activate transcription of reporter genes in HeLa cells, thus suggesting that CBP may serve as a coactivator for SREBP. </p><p>Blobel et al. (1998) found that in mouse nonhematopoietic cells, Cbp stimulated Gata1 (305371) transcriptional activity. Cbp and Gata1 also coimmunoprecipitated from nuclear extracts of mouse erythroid cells. Interaction mapping pinpointed the contact sites to the zinc finger region of Gata1 and to the E1A-binding region of Cbp. Expression of adenovirus E1A revealed that the interaction of Cbp with Gata1 in erythroid cells affected differentiation and expression of endogenous Gata1 target genes. </p><p>Weaver et al. (1998) identified CREBBP/EP300 and IRF3 (603734) as components of DRAF1 (double-stranded RNA-activated factor-1), a positive regulator of interferon-stimulated gene transcription that functions as a direct response to viral infection. </p><p>Lin et al. (2001) identified a compactly folded 46-residue domain in CBP and p300, the IRF3-binding domain (IBID), and determined its structure by nuclear magnetic resonance spectroscopy. IBID has a helical framework containing an apparently flexible polyglutamine loop that participates in ligand binding. Spectroscopic data indicated that induced folding accompanies association of IBID with its partners, which exhibit no evident sequence similarities. IBID is an important contributor to signal integration by CBP and p300. </p><p>CBP binds to the ser133 phosphorylated region of CREB via a domain called KIX (Parker et al., 1996). The phosphorylated domain of CREB was termed KID for kinase-inducible domain. Radhakrishnan et al. (1997) used nuclear magnetic resonance spectroscopy to study the molecular interactions of the KIX:KID domains of CBP and CREB, respectively. The KIX domain of CBP comprises amino acid residues 586 to 666. The KID domain of CREB comprises amino acid residues 101 to 160. The KID undergoes a coil-to-helix folding transition upon binding to KIX, forming 2 alpha helices. The amphipathic helix alpha-B of KID interacts with a hydrophobic groove defined by helices alpha-1 and alpha-3 of KIX. The other KID helix, alpha-A, contacts a different face of the alpha-3 helix. The phosphate group of the critical phosphoserine residue of KID forms a hydrogen bond to the side chain of tyr658 of KIX. The structure provides a model for interactions between other transactivation domains and their targets. </p><p>McCampbell et al. (2000) demonstrated that CREB-binding protein is incorporated into nuclear inclusions formed by polyglutamine-containing proteins in cultured cells, transgenic mice, and tissue from patients with spinal and bulbar muscular atrophy (SBMA; 313200). Soluble levels of CREB-binding protein were reduced in cells expressing expanded polyglutamine despite increased levels of CBP mRNA. Overexpression of CREBBP rescued cells from polyglutamine-mediated toxicity in neuronal cell culture. The authors proposed a CREBBP-sequestration model of polyglutamine expansion disease. </p><p>Growth factors such as epidermal growth factor (EGF; 131530) and insulin (176730) regulate development and metabolism via genes containing both POU homeodomain (PIT1; 173110) and phorbol ester (AP1, or JNK) response elements. Although CBP functions as a coactivator on these elements, the mechanism of transactivation was unclear. Zanger et al. (2001) demonstrated that CBP is recruited to these elements only after it is phosphorylated at ser436 by growth factor-dependent signaling pathways. In contrast, p300, a protein closely related to CBP that lacks this phosphorylation site, binds only weakly to the transcription complex and in a growth factor-independent manner. A small region of CBP (amino acids 312 to 440), which the authors termed the GF box, contains a potent transactivation domain and mediates this effect. Direct phosphorylation represents a novel mechanism controlling coactivator recruitment to the transcription complex. </p><p>To elucidate the molecular basis of assembling the multiprotein activation complex, Demarest et al. (2002) undertook a structural and thermodynamic analysis of the interaction domains of CBP and the activator for thyroid hormone and retinoid receptors (TRAM1; 601937). Demarest et al. (2002) demonstrated that although the isolated domains are intrinsically disordered, they combine with high affinity to form a cooperatively folded helical heterodimer. The authors concluded that their study uncovers a unique mechanism, which they termed 'synergistic folding,' through which p160 coactivators recruit CBP to allow transmission of the hormone signal to the transcriptional machinery. </p><p>Zhong et al. (2002) demonstrated that transcriptionally inactive nuclear NFKB in resting cells consists of homodimers of either p65 (164014) or p50 (164011) complexed with the histone deacetylase HDAC1 (601241). Only the p50-HDAC1 complexes bound to DNA and suppressed NFKB-dependent gene expression in unstimulated cells. Appropriate stimulation caused nuclear localization of NFKB complexes containing phosphorylated p65 that associated with CBP and displaced the p50-HDAC1 complexes. These results demonstrated that phosphorylation of p65 determines whether it associates with either CBP or HDAC1, ensuring that only p65 entering the nucleus from cytoplasmic NFKB-IKB (164008) complexes can activate transcription. </p><p>TDG (601423) initiates repair of G/T and G/U mismatches, commonly associated with CpG islands, by removing thymine and uracil moieties. Tini et al. (2002) reported that TDG associates with transcriptional coactivators CBP and p300 (602700) and that the resulting complexes are competent for both the excision step of repair and histone acetylation. TDG stimulated CBP transcriptional activity in transfected cells and reciprocally served as a substrate for CBP/p300 acetylation. This acetylation triggered release of CBP from DNA ternary complexes and also regulated recruitment of repair endonuclease APE (107748). These observations revealed a potential regulatory role for protein acetylation in base mismatch repair and a role for CBP/p300 in maintaining genomic stability. </p><p>Huntington disease (HD; 143100) belongs to the CAG repeat family of neurodegenerative diseases and is characterized by the presence of an expanded polyglutamine (polyQ) repeat in the huntingtin gene (HTT; 613004). PolyQ-expanded htt accumulates within large aggregates that are found in various subcellular compartments, but are more often localized within the nucleus. It has been suggested that the sequestration of proteins essential to cell viability may be 1 mechanism that accounts for toxicity generated by polyQ-expanded proteins. Nuclear inclusions containing polyQ-expanded htt have been shown to recruit CREBBP. In a hippocampal cell line, Jiang et al. (2003) found that toxicity within individual cells induced by polyQ-expanded htt (as revealed by a TUNEL assay) was associated with the localization of the mutant htt within either nuclear or perinuclear aggregates. However, in addition to CREBBP recruitment, CREBBP ubiquitylation and degradation were selectively enhanced by polyQ-expanded htt. Jiang et al. (2003) concluded that selected substrates may be directed to the ubiquitin/proteasome-dependent protein degradation pathway in response to polyQ-expanded htt within the nucleus. </p><p>Tsuda et al. (2003) found that SOX9 (608160) used CBP and p300 as transcriptional coactivators. SOX9 bound CBP and p300 in vitro and in vivo, and both coactivators enhanced SOX9-dependent COL2A1 (120140) promoter activity. Disruption of the CBP-SOX9 complex inhibited COL2A1 mRNA expression and differentiation of human mesenchymal stem cells into chondrocytes. </p><p>To determine the physiologic significance of the phosphorylation site at ser436 of the CREBBP protein, Zhou et al. (2004) generated knockin mice containing a ser436-to-ala mutation. They demonstrated both in vitro and in vivo that the mutant CREBBP was aberrantly recruited to CREB protein, resulting in inappropriate activation of gluconeogenesis in the fed state and glucose intolerance resulting from increased hepatic glucose production. Zhou et al. (2004) proposed that insulin signaling may directly regulate many cAMP signaling pathways at the transcriptional level by controlling CREBBP recruitment. </p><p>Turnell et al. (2005) showed that 2 anaphase-promoting complex/cyclosome (APC/C) components, APC5 (606948) and APC7 (606949), interact directly with the coactivators CBP and p300 through protein-protein interaction domains that are evolutionarily conserved in adenovirus E1A. This interaction stimulates intrinsic CBP/p300 acetyltransferase activity and potentiates CBP/p300-dependent transcription. Turnell et al. (2005) also showed that APC5 and APC7 suppress E1A-mediated transformation in a CBP/p300-dependent manner, indicating that these components of the APC/C may be targeted during cellular transformation. Furthermore, Turnell et al. (2005) established that CBP is required for APC/C function; specifically, gene ablation of CBP by RNA-mediated interference markedly reduces the E3 ubiquitin ligase activity of the APC/C and the progression of cells through mitosis. Taken together, Turnell et al. (2005) concluded that their results define discrete roles for the APC/C-CBP/p300 complexes in growth regulation. </p><p>Wang et al. (2008) showed that an RNA-binding protein, TLS (137070), serves as a key transcriptional regulatory sensor of DNA damage signals that, on the basis of its allosteric modulation by RNA, specifically binds to and inhibits CBP and p300 histone acetyltransferase activities on a repressed gene target, cyclin D1 (CCND1; 168461), in human cell lines. Recruitment of TLS to the CCND1 promoter to cause gene-specific repression is directed by single-stranded, low copy-number noncoding RNA (ncRNA) transcripts tethered to the 5-prime regulatory regions of CCND1 that are induced in response to DNA damage signals. Wang et al. (2008) suggested that signal-induced noncoding RNAs localized to regulatory regions of transcription units can act cooperatively as selective ligands, recruiting and modulating the activities of distinct classes of RNA-binding coregulators in response to specific signals, providing an unexpected noncoding RNA/RNA-binding protein-based strategy to integrate transcriptional programs. </p><p>Das et al. (2009) demonstrated that the histone acetyltransferase CBP in flies, and CBP and p300 in humans, acetylate histone H3 on lys56 (H3K56), whereas Drosophila sir2 and human SIRT1 (604479) and SIRT2 (604480) deacetylate H3K56 acetylation. The histone chaperones ASF1A (609189) in humans and Asf1 in Drosophila are required for acetylation of H3K56 in vivo, whereas the histone chaperone CAF1 (see 601245) in humans and Caf1 in Drosophila are required for the incorporation of histones bearing this mark into chromatin. Das et al. (2009) showed that, in response to DNA damage, histones bearing acetylated K56 are assembled into chromatin in Drosophila and human cells, forming foci that colocalize with sites of DNA repair. Furthermore, acetylation of H3K56 is increased in multiple types of cancer, correlating with increased levels of ASF1A in these tumors. Das et al. (2009) concluded that their identification of multiple proteins regulating the levels of H3K56 acetylation in metazoans will allow future studies of this critical and unique histone modification that couples chromatin assembly to DNA synthesis, cell proliferation, and cancer. </p><p>Using genomewide sequencing methods in mouse cortical neurons, Kim et al. (2010) identified about 12,000 neuronal activity-regulated enhancers bound by Cbp in an activity-dependent manner. At thousands of enhancers, Cbp recruited RNA polymerase II (RNAPII; see 180660). RNAPII transcribed bidirectionally a novel class of noncoding RNAs, enhancer RNAs (eRNAs), within enhancer domains defined by the presence of histone H3 (see 602810) monomethylated at lys4. The level of eRNA expression at enhancers positively correlated with the level of mRNA synthesis at nearby genes, suggesting that eRNA synthesis occurs specifically at enhancers that are actively engaged in promoting mRNA synthesis. The authors proposed that their findings reveal a novel mechanism of enhancer activation involving CBP, RNAPII, and eRNA synthesis. </p><p>In certain human cancers, the expression of critical oncogenes is driven from large regulatory elements called superenhancers, which recruit much of the cell's transcriptional apparatus and are defined by extensive acetylation of histone H3 lysine-27 (H3K27ac). Mansour et al. (2014) found that, in a subset of T-ALL cases, heterozygous somatic indels are acquired that introduce binding motifs for the MYB (189990) transcription factor in a precise noncoding site, which creates a superenhancer 7.5 kb upstream of the TAL1 (187040) oncogene. Indels at this site were referred to as 'mutation of the TAL1 enhancer,' or MuTE. MYB binds to the new site introduced by MuTE and recruits its H3K27 acetylase-binding partner CBP, as well as core components of a major leukemogenic transcriptional complex that contains RUNX1 (151385), GATA3 (131320), and TAL1 itself. Additionally, most endogenous superenhancers found in T-ALL cells are occupied by MYB and CBP, which suggests a general role for MYB in superenhancer initiation. Mansour et al. (2014) estimated that MuTE abnormalities account for about half of the cases with unexplained monoallelic overexpression of TAL1. Mansour et al. (2014) concluded that this study identified a genetic mechanism responsible for the generation of oncogenic superenhancers in malignant cells. </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>Rubinstein-Taybi Syndrome 1</em></strong></p><p>
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Petrij et al. (1995) found that all the breakpoints and microdeletions in Rubinstein-Taybi syndrome are located in 16p13.3, in a region containing the CREBBP gene. They showed, furthermore, that RSTS results not only from gross chromosomal rearrangements of 16p but also from heterozygous point mutations in the CBP gene itself (see, e.g., 600140.0001), suggesting that the loss of one functional copy of the CBP gene underlies the developmental abnormalities in RSTS, and possibly the propensity for malignancy and keloid formation. To search for mutations in RSTS patients without rearrangements, Petrij et al. (1995) used the protein truncation test. In 2 of 16 patients, a truncated protein product was found; both patients, who had classic RSTS phenotype, had a change of a glutamine codon to a stop codon (see 600140.0001 and 600140.0002). </p><p>Taine et al. (1998) found microdeletion of the RT1 probe (D16S237) in 3 of 30 French patients with RSTS. By pooling data from their study and previous series, they found the cumulative frequency of the 16p13.3 microdeletion to be 11.9% (19 in 159). Most reported microdeletions of the CREBBP gene in RSTS had been detected by FISH with a single cosmid probe specific to the 3-prime region of the gene. To explore the possibility that the rate of microdeletion-positive cases would be greater if the entire gene were evaluated, Blough et al. (2000) performed FISH on 66 patients with an established diagnosis of RSTS, using a panel of 5 cosmids spanning the CREBBP gene. Five of the 66 patients had deletions by FISH (9%), consistent with those rates reported in various series that ranged between 3% and 25%. The findings of a partial 5-prime deletion and of interstitial deletions of the gene added to the known spectrum of mutations and demonstrated the need for evaluation of the entire CREBBP gene in RSTS patients. No phenotypic differences between partial deletion, complete deletion, and nondeletion patients were observed, supporting a haploinsufficiency model for this disorder. </p><p>Petrij et al. (2000) reported diagnostic analysis of 194 patients with RSTS. Of these, 86 had previously been reported. A total of 157 individuals were tested by FISH, 23 by protein truncation test, and 14 by both methods for microdeletions and truncating mutations in CBP. Fourteen of 171 (8.2%) patients had microdeletions. Eighty-nine of the 171 were tested using 5 cosmid probes: RT1, RT100, RT102, RT191, RT203 and RT166. Eight microdeletions were found in this group, of which 4 were not deleted for RT1/RT100. Petrij et al. (2000) concluded that the use of all 5 probes is essential to detect all microdeletions in patients with clinical features of RSTS. The protein truncation test revealed truncating mutations in 4 of 37 (10.8%) cases. Petrij et al. (2000) concluded that microdeletions and truncating mutations in CBP account for approximately 20% of mutations in individuals with the RSTS phenotype. </p><p>Petrij et al. (2000) stated that the breakpoints of 6 translocations and inversions described in RSTS patients clustered in a 13-kb intronic region at the 5-prime end of the CBP gene and could theoretically result only in proteins containing the extreme N-terminal region of CREB-binding protein. Microdeletions had occurred more frequently, in approximately 10% of cases. In contrast to the previous findings, Petrij et al. (2000) showed that in one patient with a translocation t(2;16)(q36.3;p13.3), the chromosome 16 breakpoint was located about 100 kb downstream of the previously identified breakpoint cluster. Fiber FISH and Southern blot analysis were used in this determination. Western blot analysis of extracts prepared from lymphoblasts showed both a normal and an abnormal shorter protein lacking the C-terminal domain, indicating expression of both the normal and the mutant allele. The results suggested that the loss of C-terminal domains of the protein product is sufficient to cause RSTS. Furthermore, the data indicated the potential utility of Western blot analysis as an inexpensive and fast approach for screening RSTS mutations. </p><p>Murata et al. (2001) analyzed the CBP gene in 16 RSTS patients. A microdeletion was identified in 1 patient by FISH analysis; heteroallelic mutations were identified in 5 patients. These included a 2-bp and an 11-bp deletion, a 14-bp insertion, and a missense mutation resulting in an arg1378-to-pro substitution (600140.0003). This missense mutation was introduced into the recombinant mouse CBP, where it abolished the HAT activity of CBP and the ability of CBP to transactivate CREB. The authors hypothesized that loss of HAT activity of CBP may cause RSTS. They further speculated that treatment of RSTS patients with histone deacetylase inhibitors might have beneficial effects. </p><p>Among 63 patients with RSTS, Coupry et al. (2002) used several molecular techniques, including cDNA probes to search for gross gene rearrangements, intragenic microsatellite markers, and PCR with direct sequencing, to identify 22 novel point mutations in the CBP gene. In 33 patients, no abnormality in the CBP gene was detected. </p><p>Kalkhoven et al. (2003) performed mutational analysis in 39 RSTS patients and identified 8 heterozygous mutations in the HAT domain of CBP, one of which altered a conserved plant homeodomain (PHD) zinc finger amino acid (E1278K; 600140.0006), while a second deleted exon 22 (600140.0007), which encodes the central region of the PHD finger. Functional analysis revealed that these PHD finger mutants lacked in vitro acetyltransferase activity towards histones and CBP itself and displayed reduced coactivator function for the transcription factor CREB. In EBV-transformed lymphoblastoid cells from the exon 22 deletion patient, there was 50% less endogenous CBP HAT activity. The authors stressed the functional importance of the PHD finger in vivo, and implied that reduction of CBP HAT activity, as exemplified by disruption of the PHD finger, may be sufficient to cause RSTS. </p><p>In 6 (28.6%) of 21 RSTS patients in whom no point mutations had been identified, Stef et al. (2007) used comparative genomic hybridization on microarrays and quantitative multiplex fluorescent-PCR to identify deletions involving the CREBBP gene. The deletions ranged in size from 3.3 kb to 6.5 Mb; 1 patient had a deleterious duplication containing exon 16. No phenotypic differences were observed, except for 1 patient with a 6.5-Mb deletion, who had a severe phenotype and died at 34 days of life. Stef et al. (2007) concluded that CREBBP dosage anomalies constitute a common cause of the disorder and recommended high-resolution gene dosage studies of the CREBBP gene in candidate patients. </p><p>Gervasini et al. (2007) used FISH and microsatellite analysis to screen 42 Italian RSTS patients and identified deletions involving the CREBBP gene that ranged in size from 150 kb to 2.6 Mb in 6 patients. Three of the patients were low-level mosaics, with the deletion present in less than 30% of lymphocytes and in less than 20% of epithelial cells analyzed. The authors noted that, despite the small number of deleted cells in the investigated tissues, the clinical phenotype of the mosaic patients was quite typical, thus emphasizing the dose sensitivity of CREBBP. </p><p><strong><em>Menke-Hennekam Syndrome 1</em></strong></p><p>
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Menke et al. (2016) reported 10 novel missense variants (e.g., 600140.0009-600140.0012) in CREBBP, all in the last part of exon 30 or the first part of exon 31, in 11 patients with Menke-Hennekam syndrome. All mutations occurred de novo. </p><p>Menke et al. (2018) reported 9 different mutations (e.g., 600140.0010-600140.0012), 6 of them novel, in exon 30 or 31 of the CREBBP gene in 11 previously unreported patients with MKHK1. Eight mutations were missense and 1 was a 3-bp deletion; all but 1, in a patient whose parents were deceased, were shown to have occurred de novo. </p><p>Angius et al. (2019) reported an additional patient with a novel de novo missense variant (E1724K; 600140.0013) in exon 30 of CREBBP. </p><p><strong><em>Chromosome 16p13.3 Duplication Syndrome</em></strong></p><p>
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Thienpont et al. (2010) reported 12 unrelated patients with mild to moderate mental retardation and mild skeletal anomalies associated with interstitial duplication of chromosome 16p13.3 (613458). Ten of the 12 duplications occurred de novo, and 2 were inherited from unaffected parents. The duplications ranged in size, but the smallest region of overlap was 186 to 260 kb in size and included the CREBBP gene. None of the breakpoints were recurrent, arguing against nonallelic homologous recombination as a mechanism. The findings indicated that CREBBP is dosage-sensitive. Thienpont et al. (2010) estimated the frequency of CREBBP duplication to be 1 in 97,000 to 146,000 live births. </p><p><strong><em>Non-Hodgkin Lymphoma</em></strong></p><p>
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|
Pasqualucci et al. (2011) reported that the 2 most common types of B cell non-Hodgkin lymphoma (605027), follicular lymphoma and diffuse large B-cell lymphoma, harbor frequent structural alterations inactivating CREBBP and, more rarely, EP300 (602700), 2 highly related histone and nonhistone acetyltransferases (HATs) that act as transcriptional coactivators in multiple signaling pathways. Overall, about 39% of diffuse large B-cell lymphoma and 41% of follicular lymphoma cases display genomic deletions and/or somatic mutations that remove or inactivate the HAT coding domain of these 2 genes. These lesions usually affect 1 allele, suggesting that reduction in HAT dosage is important for lymphomagenesis. Pasqualucci et al. (2011) demonstrated specific defects in acetylation-mediated inactivation of the BCL6 oncoprotein (109565) and activation of the p53 tumor suppressor (191170). </p><p><strong><em>Acute Myelogenous Leukemia</em></strong></p><p>
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|
Petrij et al. (1995) noted a case of acute myeloid leukemia (601626) type M5b reported by Wessels et al. (1991) that was associated with a translocation t(8;16) whose breakpoint was located in the same region as the breakpoints in Rubinstein-Taybi syndrome-1 (RSTS1; 180849). Petrij et al. (1995) proposed that the translocation may have joined CBP to an unknown gene on chromosome 8, leading to the malignancy. </p><p>By positional cloning on chromosome 16, Borrow et al. (1996) implicated the CREB-binding protein in the M4/M5 subtype of acute myeloid leukemia. Borrow et al. (1996) also used positional cloning to identify a novel gene at the chromosome 8 breakpoint, which they termed MOZ (601408) for monocytic leukemia zinc finger protein. </p><p>Sobulo et al. (1997) stated that the recurring translocation t(11;16)(q23;p13.3) has been observed only in cases of acute leukemia or myelodysplasia secondary to therapy with drugs targeting DNA topoisomerase II (126430). Sobulo et al. (1997) showed that in 2 patients the MLL gene was fused in-frame to a different exon of the CREBBP gene, producing chimeric proteins containing the AT-hooks, methyltransferase homology domain, and transcriptional repression domain of MLL fused to the CREB-binding domain or to the bromodomain of CREBBP. Both fusion products retained the histone acetyltransferase domain of CREBBP and may lead to leukemia by promoting histone acetylation of genomic regions targeted by the MLL AT-hooks, leading to transcriptional deregulation via aberrant chromatin organization. </p><p>Panagopoulos et al. (2001) reported a novel t(10;16)(q22;p13) chromosomal translocation in a childhood acute myelogenous leukemia (AML-M5a) leading to a MORF (605880)-CBP chimera. RT-PCR experiments yielded in-frame MORF-CBP and CBP-MORF fusion transcripts. Genomic analyses revealed that the breaks were close to Alu elements in intron 16 of MORF and intron 2 of CBP and that duplications had occurred near the breakpoints. The MORF-CBP protein retained the zinc fingers, 2 nuclear localization signals, the histone acetyltransferase (HAT) domain, a portion of the acidic domain of MORF, and the CBP protein downstream of codon 29. The part of CBP encoding the RARA-binding domain, the CREB-binding domain, the 3 cys/his-rich regions, the bromodomain, the HAT domain, and the glu-rich domains was present. In the reciprocal CBP-MORF, part of the acidic domain and the C-terminal ser- and met-rich regions of MORF may be driven by the CBP promoter. </p><p>The t(8;16)(p11;p13) translocation, which is strongly associated with AML displaying monocytic differentiation, erythrophagocytosis by the leukemic cells, and a poor response to chemotherapy, fuses the CBP gene on chromosome 16p13 with the MOZ gene on chromosome 8p11. Panagopoulos et al. (2003) sequenced the breakpoints in 4 t(8;16)-positive AML cases. The breaks clustered in both CBP intron 2 and MOZ intron 16, and were close to repetitive elements; in 1 case, an Alu-Alu junction for the CBP/MOZ hybrid was identified. All 4 cases showed additional genomic events (i.e., deletions, duplications, and insertions) in the breakpoint regions in both the MOZ and CBP genes. Thus, the translocation did not originate through a simple end-to-end fusion. The findings of multiple breaks and rearrangements suggested the involvement of a damage repair mechanism in the origin of this translocation. </p><p><strong><em>Acute Lymphoblastic Leukemia</em></strong></p><p>
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Mullighan et al. (2011) found that 18.3% of relapse cases of acute lymphoblastic leukemia had sequence or deletion mutations in CREBBP and that these frequently occurred in the histone acetyltransferase domain. </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>While mapping and cloning the human CREBBP gene on 16p13.3, Giles et al. (1997) noticed an emerging pattern of relationship between this chromosome band and a region of chromosome 22q. CBP exhibits extensive homology to the adenovirus E1A-associated protein p300, whose gene (EP300; 602700) maps to 22q13 (Eckner et al., 1994; Lundblad et al., 1995). They noted that the heme oxygenase-1 gene (HMOX1; 141250) maps to 22q12 and the heme oxygenase-2 gene (HMOX2; 141251) to 16p13.3 Furthermore, the gene for phosphomannomutase-2 (PMM2; 601785) is on 16p13 and that for phosphomannomutase-1 (PMM1; 601786) is on 22q13. Sequence comparison at the amino acid level revealed that homology between these paralogous proteins is high: 63% between CBP and p300, 66% between PMM1 and PMM2, and 74% between HMOX1 and HMOX2. By examination of genome databases, e.g., OMIM, Giles et al. (1998) found 6 additional sets of paralogs mapping to 16p13 and 22q11-q13, although the extent of homology between these paralogous sets was not known. These pairs were SSTR5 (182455) and SSTR3 (182453) on 16 and 22, respectively; CSNK2A2 (115442) and CSNK1E (600863); UBE2I (601661) and UB2L3; MYH11 (160745) and MYH9 (160775); CRYM (123740) and a cluster of crystallin genes on chromosome 22, e.g., CRYBB1 (600929); IL4RA (147781) and IL2RB (146710). Giles et al. (1998) postulated that these bands show homology because of an ancestral event of the type proposed by Ohno (1993). Arguing from the fact that chromosome 14q carries SSTR1 (182451), UBE2L1 (600012), MYH6 (160710), and MYH7 (160760), whereas SSTR2 (182452), CSNK1D (600864), and CRYBA1 (123610) map to 17q, combined with the location on leukemia breakpoints, strongly suggested to Giles et al. (1998) that these gene families arose by tetraploidization resulting in members on 14q, 16p, 17q, and 22q. Genetic redundancy is potentially of great relevance to organismal evolution since it may protect against potentially harmful mutations and may provide a pool of diverse yet functionally similar proteins for further evolution. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Tanaka et al. (1997) generated Cbp +/- mice with haploinsufficiency of the Cbp protein, as demonstrated by Western blot analysis. Many of the mutant mice exhibited abnormal skeletal patterning similar to some features found in Rubinstein-Taybi syndrome, including delayed ossification of the frontal bones, enlarged anterior fontanels, and various anomalies of the sternum, rib cage, xiphoid process, and vertebrae. The mutant mice also had decreased levels of bone morphogenetic protein-7 (BMP7; 112267), a molecule believed to be part of the signaling cascade in skeletal development. Tanaka et al. (1997) found that mice homozygous for the mutation died in utero. </p><p>Kung et al. (2000) showed that Cbp +/- mice display an increased cancer risk similar to that seen in patients with RSTS. These results provided experimental evidence that CBP has tumor suppressing activity. </p><p>To identify the physiologic functions of the Cbp protein using a loss-of-function mutant, Yamauchi et al. (2002) analyzed Cbp-deficient mice. As Crebbp-null mice died during embryogenesis, they used heterozygous mice. Unexpectedly, Crebbp +/- mice showed markedly reduced weight of white adipose tissue but not of other tissues. Despite this lipodystrophy, Crebbp +/- mice showed increased insulin sensitivity and glucose tolerance and were completely protected from body weight gain induced by high-fat diet. They observed increased leptin sensitivity and increased serum adiponectin (605441) levels in Crebbp +/- mice. These increased effects of insulin-sensitizing hormones secreted from white adipose tissue may explain, at least in part, the phenotypes of Crebbp +/- mice. The study demonstrated that CBP may function as a 'master-switch' between energy storage and expenditure. </p><p>Kasper et al. (2002) demonstrated that the protein-binding KIX domains of CBP and p300 (602700) have nonredundant functions in mice. In mice homozygous for point mutations in the KIX domain of p300 designed to disrupt the binding surface for the transcription factors c-Myb (189990) and Creb, multilineage defects occur in hematopoiesis, including anemia, B-cell deficiency, thymic hypoplasia, megakaryocytosis, and thrombocytosis. By contrast, age-matched mice homozygous for identical mutations in the KIX domain of CBP are essentially normal. There is a synergistic genetic interaction between mutations in c-MYB and mutations in the KIX domain of p300, which suggests that the binding of c-MYB to this domain of p300 is crucial for the development and function of megakaryocytes. Thus, Kasper et al. (2002) concluded that conserved domains in 2 highly related coactivators have contrasting roles in hematopoiesis. </p><p>Bourtchouladze et al. (2003) reasoned that drugs that modulate CREB function by enhancing cAMP signaling might yield an effective treatment for the memory defect of CBP +/- mice. To this end, they designed a cell-based drug screen and discovered inhibitors of phosphodiesterase-4 (see 600126, for example) to be particularly effective enhancers of CREB function. They extended previous behavioral observations by showing that CBP +/- mutants have impaired long-term memory but normal learning and short-term memory in an objective recognition task. They demonstrated that the prototypic PDE4 inhibitor, rolipram, and a novel one (HT0712) abolish the long-term memory defect of CBP +/- mice. The genetic lesion in CBP acts specifically to shift the dose sensitivity for HT0712 to enhance memory formation, which conveys molecular specificity on the drug's mechanism of action. The results suggested that PDE4 inhibitors might be used to treat the cognitive dysfunction of RSTS patients. </p><p>Alarcon et al. (2004) found that transgenic mice haploinsufficient for the Cbp protein exhibited normal activity, motivation, anxiety, and working short-term memory, but had reduced long-term memory for fear and object recognition. Electrophysiologic measurements showed that the mutant mice had normal basal synaptic transmission, but had a defect in the late phase of hippocampal long-term potentiation that is dependent on transcriptional activation. Immunohistochemistry and Western blot analysis showed that the Cbp +/- mice had decreased acetylation of histone H2B (see 609904), indicating an alteration in chromatin. Both enhancement of the expression of CREB-dependent genes and inhibition of histone deacetylation ameliorated the long-term potentiation and memory defects. Alarcon et al. (2004) concluded that some of the cognitive deficits in RTS may result from the continued requirement throughout life for both functions of CBP: activation of CREB and histone acetylation with chromatin remodeling. </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>13 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 RUBINSTEIN-TAYBI SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CREBBP, GLN136TER
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<br />
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SNP: rs121434624,
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gnomAD: rs121434624,
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ClinVar: RCV000010035
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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 patient with Rubinstein-Taybi syndrome-1 (RSTS1; 180849), Petrij et al. (1995) identified a C-T transition in the CREBBP gene, resulting in a stop codon and a truncated protein product. </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 RUBINSTEIN-TAYBI SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CREBBP, GLN357TER
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<br />
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SNP: rs121434625,
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ClinVar: RCV000010036
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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 patient with Rubinstein-Taybi syndrome-1 (RSTS1; 180849), Petrij et al. (1995) identified a C-T transition in the CREBBP gene, resulting in a stop codon and a truncated protein product. In this patient, the mutation destroyed a PvuII restriction site. Since the site was found to be intact in both chromosomes of the parents, the mutation in the patient must have been de novo. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0003 RUBINSTEIN-TAYBI SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CREBBP, ARG1378PRO
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<br />
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SNP: rs121434626,
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ClinVar: RCV000010037
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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 patient with Rubinstein-Taybi syndrome-1 (180849), Murata et al. (2001) demonstrated a G-C transversion in the CREBBP gene, resulting in an arg1378-to-pro (R1378P) substitution. In a transgenic mouse model, this mutation abolished HAT activity of the CREB-binding protein. </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>.0004 RUBINSTEIN-TAYBI SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CREBBP, 2-BP DEL, NT5222
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<br />
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SNP: rs2151330140,
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ClinVar: RCV000010038
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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 patient with Rubinstein-Taybi syndrome-1 (180849), Murata et al. (2001) demonstrated a 2-bp deletion in the CREBBP gene of nucleotides 5222-5223, leading to missense translation from codons 1469-1476, followed by premature termination at codon 1477. </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>.0005 RUBINSTEIN-TAYBI SYNDROME 1, INCOMPLETE</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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CREBBP, TYR1175CYS
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<br />
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SNP: rs28937315,
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|
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ClinVar: RCV000010039, RCV004609293
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with a mild form of Rubinstein-Taybi syndrome-1 (180849), Bartsch et al. (2002) identified a 3524A-G transition in the CREBBP gene, resulting in a tyr1175-to-cys (Y1175C) substitution. The authors concluded that the missense mutation resulted in the milder phenotype. </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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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 RUBINSTEIN-TAYBI SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
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CREBBP, GLU1278LYS
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<br />
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|
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SNP: rs267606752,
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|
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ClinVar: RCV000010040, RCV000255660, RCV001260694, RCV001267080, RCV001813970, RCV002496320, RCV004742224
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Rubinstein-Taybi syndrome-1 (180849), Kalkhoven et al. (2003) identified a 3832G-A transition in the CREBBP gene, resulting in a glu1278-to-lys (E1278K) substitution at a conserved residue within the PHD finger of the HAT domain. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 RUBINSTEIN-TAYBI SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
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|
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CREBBP, IVS21, A-T, -2
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<br />
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|
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SNP: rs1567277287,
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|
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ClinVar: RCV000010041
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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 patient with Rubinstein-Taybi syndrome-1 (180849), Kalkhoven et al. (2003) identified an A-to-T transversion 2 bp 5-prime to exon 22 in the CREBBP gene. The mutation was predicted to result in aberrant splicing and loss of the 26 amino acids encoded by exon 22. These residues lie in the middle of the PHD finger of the HAT domain. Expression studies revealed loss of HAT activity in transiently transfected cells. </p>
|
|
</span>
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|
</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 RUBINSTEIN-TAYBI SYNDROME 1, INCOMPLETE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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CREBBP, THR910ALA
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<br />
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SNP: rs143247685,
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|
gnomAD: rs143247685,
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|
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ClinVar: RCV000022942, RCV000145728, RCV000421582, RCV001087789, RCV001252206, RCV002224958, RCV002311524, RCV003974853
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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 girl, her mother, and maternal grandmother with an incomplete form of Rubinstein-Taybi syndrome-1 (180849), Bartsch et al. (2010) identified a heterozygous 2728A-G transition in exon 14 of the CREBBP gene, resulting in a thr910-to-ala (T910A) substitution in a partially conserved residue. The mutation occurred outside the crucial histone acetyltransferase domain, which could explain the milder phenotype. The 12-year-old female proband had mild dysmorphic features, such as high-arched eyebrows, elongated face, prominent nose, high-arched palate, short broad thumbs, and broad halluces. She had a short attention span, dyslexia, dyscalculia, reading difficulties, and needed special teaching in language and mathematics. Her mother had similar facial features, was mildly obese, and had normal intelligence. The grandmother reportedly had a similar appearance and had not finished school. The report confirmed autosomal dominant inheritance of the disorder. </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>.0009 MENKE-HENNEKAM SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CREBBP, CYS1710ARG
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<br />
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SNP: rs1567265203,
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ClinVar: RCV000757965
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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 boy (patient 1) with Menke-Hennekam syndrome-1 (MKHK1; 618332), Menke et al. (2016) detected a heterozygous T-to-C transition at nucleotide 5128 (c.5128T-C, GRCh37) in exon 30 of the CREBBP gene resulting in a cys-to-arg substitution at codon 1710 (C1710R) in the ZNF2 domain of the protein. This de novo mutation was not present in the ESP or ExAC databases. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0010 MENKE-HENNEKAM SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CREBBP, ARG1867GLN
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<br />
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SNP: rs1131691326,
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ClinVar: RCV000493961, RCV000757966, RCV003758800
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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 girl (patient 8) with Menke-Hennekam syndrome-1 (MKHK1; 618332), Menke et al. (2016) detected a heterozygous G-to-A transition at nucleotide 5600 (c.5600G-A, GRCh37) in exon 31 of the CREBBP gene resulting in an arg-to-gln substitution at codon 1867 (R1867Q). The patient had a dizygotic twin brother with mild developmental delay. The mutation was shown to have occurred de novo and was not present in the ESP or ExAC databases. </p><p>Menke et al. (2018) detected the R1867Q mutation (c.5600G-A, NM_004380.2) in a 57-year-old man from the Netherlands (patient C16). Inheritance of the mutation could not be determined because the patient's parents were deceased. The mutation was not present in gnomAD. </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>.0011 MENKE-HENNEKAM SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CREBBP, ARG1868TRP
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<br />
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SNP: rs886039491,
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ClinVar: RCV000254930, RCV000757967, RCV002282094, RCV003156089
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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 girls (patients 9 and 10) with Menke-Hennekam syndrome-1 (MKHK1; 618332), Menke et al. (2016) detected heterozygosity for a C-to-T transition at nucleotide 5602 (c.5602C-T, GRCh37) in exon 31 of the CREBBP gene, resulting in an atg1868-to-trp (R1868W) substitution. This de novo mutation was not present in the ESP or ExAC databases. </p><p>Menke et al. (2018) found the R1868W mutation (c.5602C-T, NM_004380.2) in 3 unrelated children (patients C17, C18, and C19) with MKHK1. The mutation occurred de novo in all 3 cases and was not found in gnomAD. </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>.0012 MENKE-HENNEKAM SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CREBBP, MET1872VAL
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<br />
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SNP: rs797045037,
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ClinVar: RCV000191076, RCV000523539, RCV000757968, RCV001260745, RCV002517032, RCV003422092, RCV003458352
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</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a girl (patient 11) with Menke-Hennekam syndrome-1 (MKHK1; 618332), Menke et al. (2016) identified a heterozygous c.5614A-G transition (c.5614A-G, GRCh37) in exon 31 of the CREBBP gene that resulted in a met1872-to-val substitution (M1872V). The mutation occurred de novo and was not found in the ESP or ExAC databases. </p><p>Menke et al. (2018) identified the M1872V mutation (c.5614A-G, NM_004380.2) in a 9-year-old Norwegian boy. The mutation was shown to have occurred de novo and was not present in gnomAD. </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>.0013 MENKE-HENNEKAM SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CREBBP, GLU1724LYS
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<br />
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SNP: rs1567265131,
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|
|
ClinVar: RCV000757969, RCV003317356
|
|
|
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|
|
</span>
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|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 17-year-old Sardinian boy with Menke-Hennekam syndrome-1 (MKHK1; 618332), Angius et al. (2019) found a heterozygous c.5170G-A transition (c.5170G-A, NM_004380) in exon 30 of the CREBBP gene that resulted in a glu1724-to-lys (E1724K) substitution in the ZNF2 domain of the protein. The patient mild intellectual disability and dysmorphisms as well as obesity. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
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<p />
|
|
</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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|
Alarcon, J. M., Malleret, G., Touzani, K., Vronskaya, S., Ishii, S., Kandel, E. R., Barco, A.
|
|
<strong>Chromatin acetylation, memory, and LTP are impaired in CBP+/- mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration.</strong>
|
|
Neuron 42: 947-959, 2004.
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[PubMed: 15207239]
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[Full Text: https://doi.org/10.1016/j.neuron.2004.05.021]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Angius, A., Uva, P., Oppo, M., Persico, I., Onano, S., Olla, S., Pes, V., Perria, C., Cuccuru, G., Atzeni, R., Serra, G., Cucca, F., Sotgiu, S., Hennekam, R. C., Crisponi, L.
|
|
<strong>Confirmation of a new phenotype in an individual with a variant in the last part of exon 30 of CREBBP.</strong>
|
|
Am. J. Med. Genet. 179A: 634-638, 2019.
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[PubMed: 30737887]
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[Full Text: https://doi.org/10.1002/ajmg.a.61052]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Arias, J., Alberts, A. S., Brindle, P., Claret, F. X., Smeal, T., Karin, M., Feramisco, J., Montminy, M.
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<strong>Activation of cAMP and mitogen responsive genes relies on a common nuclear factor.</strong>
|
|
Nature 370: 226-229, 1994.
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[PubMed: 8028671]
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[Full Text: https://doi.org/10.1038/370226a0]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Bartsch, O., Kress, W., Kempf, O., Lechno, S., Haaf, T., Zechner, U.
|
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<strong>Inheritance and variable expression in Rubinstein-Taybi syndrome.</strong>
|
|
Am. J. Med. Genet. 152A: 2254-2261, 2010.
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[PubMed: 20684013]
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[Full Text: https://doi.org/10.1002/ajmg.a.33598]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Bartsch, O., Locher, K., Meinecke, P., Kress, W., Seemanova, E., Wagner, A., Ostermann, K., Rodel, G.
|
|
<strong>Molecular studies in 10 cases of Rubinstein-Taybi syndrome, including a mild variant showing a missense mutation in codon 1175 of CREBBP.</strong>
|
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J. Med. Genet. 39: 496-501, 2002.
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[PubMed: 12114483]
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[Full Text: https://doi.org/10.1136/jmg.39.7.496]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Blobel, G. A., Nakajima, T., Eckner, R., Montminy, M., Orkin, S. H.
|
|
<strong>CREB-binding protein cooperates with transcription factor GATA-1 and is required for erythroid differentiation.</strong>
|
|
Proc. Nat. Acad. Sci. 95: 2061-2066, 1998.
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[PubMed: 9482838]
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[Full Text: https://doi.org/10.1073/pnas.95.5.2061]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Blough, R. I., Petrij, F., Dauwerse, J. G., Milatovich-Cherry, A., Weiss, L., Saal, H. M., Rubinstein, J. H.
|
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<strong>Variation in microdeletions of the cyclic AMP-responsive element-binding protein gene at chromosome band 16p13.3 in the Rubinstein-Taybi syndrome.</strong>
|
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Am. J. Med. Genet. 90: 29-34, 2000.
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[PubMed: 10602114]
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[Full Text: https://doi.org/10.1002/(sici)1096-8628(20000103)90:1<29::aid-ajmg6>3.0.co;2-z]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Borrow, J., Stanton, V. P., Jr., Andresen, J. M., Becher, R., Behm, F. G., Chaganti, R. S. K., Civin, C. I., Disteche, C., Dube, I., Frischauf, A. M., Horsman, D., Mitelman, F., Volinia, S., Watmore, A. E., Housman, D. E.
|
|
<strong>The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein.</strong>
|
|
Nature Genet. 14: 33-41, 1996.
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[PubMed: 8782817]
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[Full Text: https://doi.org/10.1038/ng0996-33]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Bourtchouladze, R., Lidge, R., Catapano, R., Stanley, J., Gossweiler, S., Romashko, D., Scott, R., Tully, T.
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<strong>A mouse model of Rubinstein-Taybi syndrome: defective long-term memory is ameliorated by inhibitors of phosphodiesterase 4.</strong>
|
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Proc. Nat. Acad. Sci. 100: 10518-10522, 2003.
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[PubMed: 12930888]
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[Full Text: https://doi.org/10.1073/pnas.1834280100]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Chen, X.-N., Korenberg, J. R.
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<strong>Localization of human CREBBP (CREB binding protein) to 16p13.3 by fluorescence in situ hybridization.</strong>
|
|
Cytogenet. Cell Genet. 71: 56-57, 1995.
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[PubMed: 7606928]
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[Full Text: https://doi.org/10.1159/000134062]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Chrivia, J. C., Kwok, R. P. S., Lamb, N., Hagiwara, M., Montminy, M. R., Goodman, R. H.
|
|
<strong>Phosphorylated CREB binds specifically to the nuclear protein CBP.</strong>
|
|
Nature 365: 855-859, 1993.
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[PubMed: 8413673]
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[Full Text: https://doi.org/10.1038/365855a0]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Coupry, I., Roudaut, C., Stef, M., Delrue, M.-A., Marche, M., Burgelin, I., Taine, L., Cruaud, C., Lacombe, D., Arveiler, B.
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<strong>Molecular analysis of the CBP gene in 60 patients with Rubinstein-Taybi syndrome.</strong>
|
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J. Med. Genet. 39: 415-421, 2002.
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[PubMed: 12070251]
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[Full Text: https://doi.org/10.1136/jmg.39.6.415]
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|
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Das, C., Lucia, M. S., Hansen, K. C., Tyler, J. K.
|
|
<strong>CBP/p300-mediated acetylation of histone H3 on lysine56.</strong>
|
|
Nature 459: 113-117, 2009. Note: Erratum: Nature 460: 1164 only, 2009.
|
|
|
|
|
|
[PubMed: 19270680]
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|
|
[Full Text: https://doi.org/10.1038/nature07861]
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|
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Demarest, S. J., Martinez-Yamout, M., Chung, J., Chen, H., Xu, W., Dyson, H. J., Evans, R. M., Wright, P. E.
|
|
<strong>Mutual synergistic folding in recruitment of CBP/p300 by p160 nuclear receptor coactivators.</strong>
|
|
Nature 415: 549-553, 2002.
|
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|
|
|
|
[PubMed: 11823864]
|
|
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|
|
[Full Text: https://doi.org/10.1038/415549a]
|
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|
|
</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Eckner, R., Ewen, M. E., Newsome, D., Gerdes, M., DeCaprio, J. A., Lawrence, J. B., Livingston, D. M.
|
|
<strong>Molecular cloning and functional analysis of the adenovirus E1A-associated 300-kD protein (p300) reveals a protein with properties of a transcriptional adaptor.</strong>
|
|
Genes Dev. 8: 869-884, 1994.
|
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|
|
|
|
[PubMed: 7523245]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1101/gad.8.8.869]
|
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|
|
</p>
|
|
</li>
|
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gervasini, C., Castronovo, P., Bentivegna, A., Mottadelli, F., Faravelli, F., Giovannucci-Uzielli, M. L., Pessagno, A., Lucci-Cordisco, E., Pinto, A. M., Salviati, L., Selicorni, A., Tenconi, R., Neri, G., Larizza, L.
|
|
<strong>High frequency of mosaic CREBBP deletions in Rubinstein-Taybi syndrome patients and mapping of somatic and germ-line breakpoints.</strong>
|
|
Genomics 90: 567-573, 2007.
|
|
|
|
|
|
[PubMed: 17855048]
|
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|
|
[Full Text: https://doi.org/10.1016/j.ygeno.2007.07.012]
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</p>
|
|
</li>
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<li>
|
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<p class="mim-text-font">
|
|
Giles, R. H., Dauwerse, H. G., van Ommen, G.-J. B., Breuning, M. H.
|
|
<strong>Do human chromosomal bands 16p13 and 22q11-13 share ancestral origins? (Letter)</strong>
|
|
Am. J. Hum. Genet. 63: 1240-1242, 1998.
|
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|
|
[PubMed: 9758602]
|
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|
|
[Full Text: https://doi.org/10.1086/302044]
|
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|
|
</p>
|
|
</li>
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<li>
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Zhou, X. Y., Shibusawa, N., Naik, K., Porras, D., Temple, K., Ou, H., Kaihara, K., Roe, M. W., Brady, M. J., Wondisford, F. E.
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Matthew B. Gross - updated : 01/14/2025<br>Ada Hamosh - updated : 02/22/2019<br>Ada Hamosh - updated : 01/08/2015<br>Cassandra L. Kniffin - updated : 6/20/2011<br>Ada Hamosh - updated : 6/14/2011<br>Cassandra L. Kniffin - updated : 6/21/2010<br>Patricia A. Hartz - updated : 12/8/2009<br>Ada Hamosh - updated : 9/9/2009<br>Ada Hamosh - updated : 6/4/2009<br>Ada Hamosh - updated : 8/29/2008<br>Ada Hamosh - updated : 3/7/2008<br>Marla J. F. O'Neill - updated : 12/21/2007<br>Cassandra L. Kniffin - updated : 8/13/2007<br>Ada Hamosh - updated : 1/30/2006<br>Cassandra L. Kniffin - updated : 5/4/2005<br>George E. Tiller - updated : 1/6/2005<br>George E. Tiller - updated : 10/26/2004<br>Marla J. F. O'Neill - updated : 5/19/2004<br>Cassandra L. Kniffin - reorganized : 11/19/2003<br>Victor A. McKusick - updated : 10/10/2003<br>Patricia A. Hartz - updated : 3/11/2003<br>Victor A. McKusick - updated : 2/11/2003<br>Ada Hamosh - updated : 11/12/2002<br>Stylianos E. Antonarakis - updated : 9/23/2002<br>Ada Hamosh - updated : 2/7/2002<br>Victor A. McKusick - updated : 1/22/2002<br>Stylianos E. Antonarakis - updated : 11/5/2001<br>George E. Tiller - updated : 10/10/2001<br>George E. Tiller - updated : 4/24/2001<br>Stylianos E. Antonarakis - updated : 4/16/2001<br>George E. Tiller - updated : 11/17/2000<br>Michael J. Wright - updated : 8/10/2000<br>Paul J. Converse - updated : 7/7/2000<br>Victor A. McKusick - updated : 4/25/2000<br>Victor A. McKusick - updated : 1/13/2000<br>Patti M. Sherman - updated : 4/16/1999<br>Ada Hamosh - updated : 3/25/1999<br>Victor A. McKusick - updated : 10/23/1998<br>Victor A. McKusick - updated : 8/17/1998<br>Stylianos E. Antonarakis - updated : 1/23/1998<br>Ethylin Wang Jabs - updated : 11/18/1997<br>Victor A. McKusick - updated : 9/10/1997<br>Mark H. Paalman - updated : 8/31/1996
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