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Entry
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- *600856 - CYCLIN-DEPENDENT KINASE INHIBITOR 1C; CDKN1C
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*600856</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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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<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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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/600856">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000129757;t=ENST00000440480" 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=1028" 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=600856" 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 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=ENSG00000129757;t=ENST00000440480" 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_000076,NM_001122630,NM_001122631,NM_001362474,NM_001362475" 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_001122630" 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=600856" 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=02913&isoform_id=02913_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/CDKN1C" 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/790248,992946,1213448,1705731,1772490,4557441,45710023,119622929,119622930,169790899,169790903,172034814,1378577807,1379048501" 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/P49918" 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=1028" 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=ENSG00000129757;t=ENST00000440480" 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=CDKN1C" 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=CDKN1C" 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+1028" 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/CDKN1C" 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:1028" 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/1028" 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=chr11&hgg_gene=ENST00000440480.8&hgg_start=2883218&hgg_end=2885775&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:1786" 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://medlineplus.gov/genetics/gene/cdkn1c" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=600856[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=600856[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/CDKN1C/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/ENSG00000129757" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.gwascentral.org/search?q=CDKN1C" 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=CDKN1C" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=CDKN1C&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/PA26320" 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:1786" 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/FBgn0010316.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:104564" 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/CDKN1C#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:104564" 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/1028/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=1028" 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=WBGene00000517;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-040123-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:1028" 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=CDKN1C&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 702384004, 81780002<br />
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<strong>ICD10CM:</strong> Q87.3<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
|
600856
|
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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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CYCLIN-DEPENDENT KINASE INHIBITOR 1C; CDKN1C
|
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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">
|
|
p57(KIP2)<br />
|
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KIP2
|
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</span>
|
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=CDKN1C" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">CDKN1C</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/11/86?start=-3&limit=10&highlight=86">11p15.4</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr11:2883218-2885775&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'})">11:2,883,218-2,885,775</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=130650,614732" 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/11/86?start=-3&limit=10&highlight=86">
|
|
11p15.4
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Beckwith-Wiedemann syndrome
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/130650"> 130650 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
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|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
IMAGE syndrome
|
|
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/614732"> 614732 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
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<p>The CDKN1C gene encodes p57(KIP2), a potent tight-binding inhibitor of several G1 cyclin/Cdk complexes and a negative regulator of cell proliferation (<a href="#17" class="mim-tip-reference" title="Lee, M.-H., Reynisdottir, I., Massague, J. <strong>Cloning of p57(KIP2), a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution.</strong> Genes Dev. 9: 639-649, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7729683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7729683</a>] [<a href="https://doi.org/10.1101/gad.9.6.639" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7729683">Lee et al., 1995</a>). The CDKN1C gene is paternally imprinted, with preferential expression of the maternal allele (<a href="#11" class="mim-tip-reference" title="Hatada, I., Mukai, T. <strong>Genomic imprinting of p57(KIP2), a cyclin-dependent kinase inhibitor, in mouse.</strong> Nature Genet. 11: 204-206, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550351</a>] [<a href="https://doi.org/10.1038/ng1095-204" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550351">Hatada and Mukai, 1995</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7729683+7550351" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#17" class="mim-tip-reference" title="Lee, M.-H., Reynisdottir, I., Massague, J. <strong>Cloning of p57(KIP2), a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution.</strong> Genes Dev. 9: 639-649, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7729683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7729683</a>] [<a href="https://doi.org/10.1101/gad.9.6.639" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7729683">Lee et al. (1995)</a> and <a href="#18" class="mim-tip-reference" title="Matsuoka, S., Edwards, M. C., Bai, C., Parker, S., Zhang, P., Baldini, A., Harper, J. W., Elledge, S. J. <strong>p57(KIP2), a structurally distinct member of the p21(CIP1) Cdk inhibitor family, is a candidate tumor suppressor gene.</strong> Genes Dev. 9: 650-662, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7729684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7729684</a>] [<a href="https://doi.org/10.1101/gad.9.6.650" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7729684">Matsuoka et al. (1995)</a> reported that the human p57(KIP2) gene encodes a 316-amino acid protein consisting of 3 structurally distinct domains, including an N-terminal CDK inhibitory domain with significant similarity to p21(CIP1) (<a href="/entry/116899">116899</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7729683+7729684" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 quantitative RT-PCR, <a href="#3" class="mim-tip-reference" title="Arboleda, V. A., Lee, H., Parnaik, R., Fleming, A., Banerjee, A., Ferraz-de-Souza, B., Delot, E. C., Rodriguez-Fernandez, I. A., Braslavsky, D., Bergada, I., Dell'Angelica, E. C., Nelson, S. F., Martinez-Agosto, J. A., Achermann, J. C., Vilain, E. <strong>Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome.</strong> Nature Genet. 44: 788-792, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22634751/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22634751</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22634751[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2275" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22634751">Arboleda et al. (2012)</a> demonstrated that expression of CDKN1C is greater in adrenal tissue than in brain or muscle during early human development. Immunohistochemistry showed the strongest expression of CDKN1C within a subset of cells in the subcapsular or developing definitive zone of the adrenal gland. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22634751" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The CDKN1C gene contains 3 exons (<a href="#24" class="mim-tip-reference" title="Tokino, T., Urano, T., Furuhata, T., Matsushima, M., Miyatsu, T., Sasaki, S., Nakamura, Y. <strong>Characterization of the human p57(KIP2) gene: alternative splicing, insertion/deletion polymorphisms in VNTR sequences in the coding region, and mutational analysis.</strong> Hum. Genet. 97: 625-631, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8655143/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8655143</a>] [<a href="https://doi.org/10.1007/BF02281873" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8655143">Tokino et al., 1996</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8655143" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#18" class="mim-tip-reference" title="Matsuoka, S., Edwards, M. C., Bai, C., Parker, S., Zhang, P., Baldini, A., Harper, J. W., Elledge, S. J. <strong>p57(KIP2), a structurally distinct member of the p21(CIP1) Cdk inhibitor family, is a candidate tumor suppressor gene.</strong> Genes Dev. 9: 650-662, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7729684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7729684</a>] [<a href="https://doi.org/10.1101/gad.9.6.650" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7729684">Matsuoka et al. (1995)</a> demonstrated that the CDKN1C gene is located on chromosome 11p15.5, a region implicated in both sporadic cancers and Beckwith-Wiedemann syndrome, a familial cancer syndrome, making it a tumor suppressor candidate. Several types of childhood tumors, including Wilms tumor (<a href="/entry/194071">194071</a>), adrenocortical carcinoma (<a href="/entry/202300">202300</a>), and rhabdomyosarcoma (<a href="/entry/268210">268210</a>), display a specific loss of maternal 11p15 alleles, suggesting that genomic imprinting plays an important role. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7729684" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#11" class="mim-tip-reference" title="Hatada, I., Mukai, T. <strong>Genomic imprinting of p57(KIP2), a cyclin-dependent kinase inhibitor, in mouse.</strong> Nature Genet. 11: 204-206, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550351</a>] [<a href="https://doi.org/10.1038/ng1095-204" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550351">Hatada and Mukai (1995)</a> showed that a mouse homolog of p57(KIP2) is genomically imprinted. The paternally inherited allele is transcriptionally repressed and methylated. The mouse gene maps to the distal region of chromosome 7, within a cluster of imprinted genes, including insulin-like growth factor-2 (IGF2; <a href="/entry/147470">147470</a>) and H19 (<a href="/entry/103280">103280</a>). <a href="#19" class="mim-tip-reference" title="Matsuoka, S., Thompson, J. S., Edwards, M. C., Barletta, J. M., Grundy, P., Kalikin, L. M., Harper, J. W., Elledge, S. J., Feinberg, A. P. <strong>Imprinting of the gene encoding a human cyclin-dependent kinase inhibitor, p57(KIP2), on chromosome 11p15.</strong> Proc. Nat. Acad. Sci. 93: 3026-3030, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8610162/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8610162</a>] [<a href="https://doi.org/10.1073/pnas.93.7.3026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8610162">Matsuoka et al. (1996)</a> demonstrated that the p57(KIP2) gene is imprinted in the human also. It is situated 500 kb centromeric to the IGF2 gene. The maternal allele is preferentially expressed; however, the imprint is not absolute, as the paternal allele is also expressed at low levels in most tissues and at levels comparable to the maternal allele in fetal brain and some embryonal tumors. It appears to lie in a domain containing other imprinted genes. <a href="#19" class="mim-tip-reference" title="Matsuoka, S., Thompson, J. S., Edwards, M. C., Barletta, J. M., Grundy, P., Kalikin, L. M., Harper, J. W., Elledge, S. J., Feinberg, A. P. <strong>Imprinting of the gene encoding a human cyclin-dependent kinase inhibitor, p57(KIP2), on chromosome 11p15.</strong> Proc. Nat. Acad. Sci. 93: 3026-3030, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8610162/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8610162</a>] [<a href="https://doi.org/10.1073/pnas.93.7.3026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8610162">Matsuoka et al. (1996)</a> commented that establishment of an imprint may be coordinately regulated throughout the entire domain, as suggested by similar tissue-specific expression and imprinting patterns of IGF2, H19, and p57(KIP2) genes, while loss of imprinting (LOI) may not necessarily affect the entire region. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8610162+7550351" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Du, M., Beatty, L. G., Zhou, W., Lew, J., Schoenherr, C., Weksberg, R., Sadowski, P. D. <strong>Insulator and silencer sequences in the imprinted region of human chromosome 11p15.5.</strong> Hum. Molec. Genet. 12: 1927-1939, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12874112/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12874112</a>] [<a href="https://doi.org/10.1093/hmg/ddg194" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12874112">Du et al. (2003)</a> confirmed the existence of insulators in the differentially methylated region (DMR) of the H19 gene and reported 2 insulators in the IGF2 gene. They also found 2 novel silencer sequences: 1 in KvDMR, a region that is thought to contain the promoter for the KCNQ1OT1 (<a href="/entry/604115">604115</a>) transcript, and the other in CDKN1C. The authors demonstrated binding of the zinc finger protein CTCF (<a href="/entry/604167">604167</a>) in vitro to all the insulator and silencer sequences detected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12874112" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using primary human hematopoietic cells and microarray analysis, <a href="#22" class="mim-tip-reference" title="Scandura, J. M., Boccuni, P., Massague, J., Nimer, S. D. <strong>Transforming growth factor beta-induced cell cycle arrest of human hematopoietic cells requires p57KIP2 upregulation.</strong> Proc. Nat. Acad. Sci. 101: 15231-15236, 2004. Note: Erratum: Proc. Nat. Acad. Sci. 101: 16707 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15477587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15477587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15477587[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.0406771101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15477587">Scandura et al. (2004)</a> identified p57(KIP2) as the only cyclin-dependent kinase inhibitor induced by TGF-beta (<a href="/entry/190180">190180</a>). Upregulation of p57 mRNA and protein occurred before TGF-beta-induced G1 cell cycle arrest, required transcription, and was mediated via a highly conserved region of the proximal p57 promoter. Upregulation of p57 was essential for TGF-beta-induced cell cycle arrest in these cells, since 2 different small interfering RNAs that prevented p57 upregulation blocked the cytostatic effects of TGF-beta on the hematopoietic cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15477587" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 DNA from Beckwith-Wiedemann syndrome (BWS; <a href="/entry/130650">130650</a>) patients with downregulated CDKN1C and normal methylation at KvDMR1, <a href="#6" class="mim-tip-reference" title="Diaz-Meyer, N., Yang, Y., Sait, S. N., Maher, E. R., Higgins, M. J. <strong>Alternative mechanisms associated with silencing of CDKN1C in Beckwith-Wiedemann syndrome.</strong> J. Med. Genet. 42: 648-655, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16061564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16061564</a>] [<a href="https://doi.org/10.1136/jmg.2004.030593" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16061564">Diaz-Meyer et al. (2005)</a> observed depletion of dimethylated H3-K4 (see <a href="/entry/602810">602810</a>) and enrichment of dimethylated H3-K9 and HP1-gamma (<a href="/entry/604477">604477</a>) at the CDKN1C promoter, suggesting that in these cases gene silencing is associated with repressive chromatin changes. <a href="#6" class="mim-tip-reference" title="Diaz-Meyer, N., Yang, Y., Sait, S. N., Maher, E. R., Higgins, M. J. <strong>Alternative mechanisms associated with silencing of CDKN1C in Beckwith-Wiedemann syndrome.</strong> J. Med. Genet. 42: 648-655, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16061564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16061564</a>] [<a href="https://doi.org/10.1136/jmg.2004.030593" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16061564">Diaz-Meyer et al. (2005)</a> concluded that CDKN1C may be downregulated by multiple mechanisms including some that do not involve promoter methylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16061564" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using DNA microarrays to compare gene expression patterns in normal human placenta with those in other tissues, <a href="#23" class="mim-tip-reference" title="Sood, R., Zehnder, J. L., Druzin, M. L., Brown, P. O. <strong>Gene expression patterns in human placenta.</strong> Proc. Nat. Acad. Sci. 103: 5478-5483, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16567644/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16567644</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16567644[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.0508035103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16567644">Sood et al. (2006)</a> found that several genes involved in growth and tissue remodeling were expressed at relatively higher levels in the villus sections of placenta compared with other tissues. These included GPC3 (<a href="/entry/300037">300037</a>), CDKN1C, and IGF2. The GPC3 and CDKN1C genes are mutated in patients with Simpson-Golabi-Behmel syndrome (<a href="/entry/312870">312870</a>) and BWS, respectively, both fetal-placental overgrowth syndromes. In contrast, loss of IGF2 is associated with fetal growth restriction in mice. The relatively higher expression of genes that both promote and suppress growth suggested to <a href="#23" class="mim-tip-reference" title="Sood, R., Zehnder, J. L., Druzin, M. L., Brown, P. O. <strong>Gene expression patterns in human placenta.</strong> Proc. Nat. Acad. Sci. 103: 5478-5483, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16567644/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16567644</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16567644[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.0508035103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16567644">Sood et al. (2006)</a> tight and local regulation of the pathways that control placental development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16567644" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In mice, adult cardiomyocytes primarily express alpha-myosin heavy chain (alpha-MHC, also known as Myh6; <a href="/entry/160710">160710</a>), whereas embryonic cardiomyocytes express beta-MHC (also known as Myh7; <a href="/entry/160760">160760</a>). Cardiac stress triggers adult hearts to undergo hypertrophy and a shift from alpha-MHC to fetal beta-MHC expression. <a href="#10" class="mim-tip-reference" title="Hang, C. T., Yang, J., Han, P., Cheng, H.-L., Shang, C., Ashley, E., Zhou, B., Chang, C.-P. <strong>Chromatin regulation by Brg1 underlies heart muscle development and disease.</strong> Nature 466: 62-67, 2010. Note: Erratum: Nature 475: 532 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20596014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20596014</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20596014[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/nature09130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20596014">Hang et al. (2010)</a> showed that BRG1 (<a href="/entry/603254">603254</a>), a chromatin-remodeling protein, has a critical role in regulating cardiac growth, differentiation, and gene expression. In embryos, Brg1 promotes myocyte proliferation by maintaining Bmp10 (<a href="/entry/608748">608748</a>) and suppressing p57(kip2) expression. It preserves fetal cardiac differentiation by interacting with histone deacetylases (HDACs; see <a href="/entry/601241">601241</a>) and poly(ADP ribose) polymerase (PARP; <a href="/entry/173870">173870</a>) to repress alpha-MHC and activate beta-MHC. In adults, Brg1 (also known as Smarca4) is turned off in cardiomyocytes. It is reactivated by cardiac stresses and forms a complex with its embryonic partners, HDAC and PARP, to induce a pathologic alpha-MHC-to-beta-MHC shift. Preventing Brg1 reexpression decreases hypertrophy and reverses this MHC switch. BRG1 is activated in certain patients with hypertrophic cardiomyopathy, its level correlating with disease severity and MHC changes. <a href="#10" class="mim-tip-reference" title="Hang, C. T., Yang, J., Han, P., Cheng, H.-L., Shang, C., Ashley, E., Zhou, B., Chang, C.-P. <strong>Chromatin regulation by Brg1 underlies heart muscle development and disease.</strong> Nature 466: 62-67, 2010. Note: Erratum: Nature 475: 532 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20596014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20596014</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20596014[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/nature09130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20596014">Hang et al. (2010)</a> concluded that their studies showed that BRG1 maintains cardiomyocytes in an embryonic state, and demonstrated an epigenetic mechanism by which 3 classes of chromatin-modifying factors, BRG1, HDAC, and PARP, cooperate to control developmental and pathologic gene expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20596014" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Hydatidiform mole (HYDM; <a href="/entry/231090">231090</a>) is an abnormal gestation characterized by trophoblast hyperplasia and overgrowth of placental villi. The genetic basis in the vast majority of cases is an excess of paternal to maternal genomes, suggesting that global misexpression of imprinted genes is the common underlying molecular mechanism. Although most cases of complete HYDM are androgenetic in origin, a rare, frequently familial, biparental variant has been described. In a series of patients with biparental complete HYDM, <a href="#8" class="mim-tip-reference" title="Fisher, R. A., Hodges, M. D., Rees, H. C., Sebire, N. J., Seckl, M. J., Newlands, E. S., Genest, D. R., Castrillon, D. H. <strong>The maternally transcribed gene p57(KIP2) (CDNK1C) is abnormally expressed in both androgenetic and biparental complete hydatidiform moles.</strong> Hum. Molec. Genet. 11: 3267-3272, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12471053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12471053</a>] [<a href="https://doi.org/10.1093/hmg/11.26.3267" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12471053">Fisher et al. (2002)</a> observed dramatic underexpression of CDKN1C identical to the pattern seen in complete HYDM of androgenetic origin. The series included 2 sisters, both of whom had biparental complete HYDM. Genotyping of this family identified a 15-cM region of homozygosity for 19q13.3-q13.4 similar to that found in 3 other families with recurrent biparental complete HYDM. <a href="#8" class="mim-tip-reference" title="Fisher, R. A., Hodges, M. D., Rees, H. C., Sebire, N. J., Seckl, M. J., Newlands, E. S., Genest, D. R., Castrillon, D. H. <strong>The maternally transcribed gene p57(KIP2) (CDNK1C) is abnormally expressed in both androgenetic and biparental complete hydatidiform moles.</strong> Hum. Molec. Genet. 11: 3267-3272, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12471053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12471053</a>] [<a href="https://doi.org/10.1093/hmg/11.26.3267" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12471053">Fisher et al. (2002)</a> concluded that biparental complete HYDM, like complete HYDM of androgenetic origin, may result from abnormal expression of imprinted genes (such as CDKN1C), and that a locus on 19q13.3-q13.4 may regulate expression of imprinted genes on other chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12471053" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Beckwith-Wiedemann Syndrome</em></strong></p><p>
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<a href="#13" class="mim-tip-reference" title="Hatada, I., Ohashi, H., Fukushima, Y., Kaneko, Y., Inoue, M., Komoto, Y., Okada, A., Ohishi, S., Nabetani, A., Morisaki, H., Nakayama, M., Niikawa, M,, Mukai, T. <strong>An imprinted gene p57(KIP2) is mutated in Beckwith-Wiedemann syndrome.</strong> Nature Genet. 14: 171-173, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8841187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8841187</a>] [<a href="https://doi.org/10.1038/ng1096-171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8841187">Hatada et al. (1996)</a> studied the p57(KIP2) gene in DNA samples from 9 unrelated Japanese patients with Beckwith-Wiedemann syndrome. They detected mutations in 2 BWS patients. In a 7-year-old boy with Beckwith Wiedemann syndrome (diagnosed on the basis of increased birth weight, omphalocele, macroglossia, intractable neonatal hypoglycemia, facial nevus flammeus, and earlobe grooves), PCR amplification and direct sequencing analysis led to identification of a heterozygous C-to-T transition at nucleotide 399, changing glutamine (CAG) to a termination codon (TAG) at position 47 (<a href="#0001">600856.0001</a>). The mother was also heterozygous for the mutation but had inherited it from her father. She was phenotypically normal, since p57(KIP2) is expressed from the maternal allele (which was normal in her case). <a href="#13" class="mim-tip-reference" title="Hatada, I., Ohashi, H., Fukushima, Y., Kaneko, Y., Inoue, M., Komoto, Y., Okada, A., Ohishi, S., Nabetani, A., Morisaki, H., Nakayama, M., Niikawa, M,, Mukai, T. <strong>An imprinted gene p57(KIP2) is mutated in Beckwith-Wiedemann syndrome.</strong> Nature Genet. 14: 171-173, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8841187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8841187</a>] [<a href="https://doi.org/10.1038/ng1096-171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8841187">Hatada et al. (1996)</a> also described a p57(KIP2) mutation in a 3-month-old girl with BWS. This patient was heterozygous for a T-to-AG change at nucleotide 1086 that modified the 9 amino acids downstream and resulted in a premature translation termination (<a href="#0002">600856.0002</a>). In one other patient <a href="#13" class="mim-tip-reference" title="Hatada, I., Ohashi, H., Fukushima, Y., Kaneko, Y., Inoue, M., Komoto, Y., Okada, A., Ohishi, S., Nabetani, A., Morisaki, H., Nakayama, M., Niikawa, M,, Mukai, T. <strong>An imprinted gene p57(KIP2) is mutated in Beckwith-Wiedemann syndrome.</strong> Nature Genet. 14: 171-173, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8841187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8841187</a>] [<a href="https://doi.org/10.1038/ng1096-171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8841187">Hatada et al. (1996)</a> demonstrated reduced expression of the p57(KIP2) gene in adrenal gland. <a href="#13" class="mim-tip-reference" title="Hatada, I., Ohashi, H., Fukushima, Y., Kaneko, Y., Inoue, M., Komoto, Y., Okada, A., Ohishi, S., Nabetani, A., Morisaki, H., Nakayama, M., Niikawa, M,, Mukai, T. <strong>An imprinted gene p57(KIP2) is mutated in Beckwith-Wiedemann syndrome.</strong> Nature Genet. 14: 171-173, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8841187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8841187</a>] [<a href="https://doi.org/10.1038/ng1096-171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8841187">Hatada et al. (1996)</a> concluded that their studies provided evidence for a new mechanism for producing a phenotype with dominant transmission with little or no gene product: one allele with an inactive product is expressed and the other allele is repressed by genomic imprinting. <a href="#13" class="mim-tip-reference" title="Hatada, I., Ohashi, H., Fukushima, Y., Kaneko, Y., Inoue, M., Komoto, Y., Okada, A., Ohishi, S., Nabetani, A., Morisaki, H., Nakayama, M., Niikawa, M,, Mukai, T. <strong>An imprinted gene p57(KIP2) is mutated in Beckwith-Wiedemann syndrome.</strong> Nature Genet. 14: 171-173, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8841187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8841187</a>] [<a href="https://doi.org/10.1038/ng1096-171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8841187">Hatada et al. (1996)</a> commented that other loci may possibly be involved in BWS since there are 3 other known balanced translocations leading to BWS which map several megabases from the p57(KIP2) region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8841187" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 complete sequencing of the coding exons and intron/exon junctions of the CDKN1C gene, <a href="#20" class="mim-tip-reference" title="O'Keefe, D., Dao, D., Zhao, L., Sanderson, R., Warburton, D., Weiss, L., Anyane-Yeboa, K., Tycko, B. <strong>Coding mutations in p57(KIP2) are present in some cases of Beckwith-Wiedemann syndrome but are rare or absent in Wilms tumors.</strong> Am. J. Hum. Genet. 61: 295-303, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9311733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9311733</a>] [<a href="https://doi.org/10.1086/514854" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9311733">O'Keefe et al. (1997)</a> found a maternally transmitted coding mutation in the CDK-inhibitor domain of the KIP2 gene in 1 of 5 cases of BWS. The mutation was an in-frame 3-amino acid deletion that significantly reduced but did not fully abrogate growth-suppressive activity in transfection assay. In contrast, no somatic coding mutations from KIP2 were found in a set of 12 primary Wilms tumors enriched for cases that expressed KIP2 mRNA, including cases with and without 11p15.5 loss of heterozygosity. <a href="#16" class="mim-tip-reference" title="Lee, M. P., DeBaun, M., Randhawa, G., Reichard, B. A., Elledge, S. J., Feinberg, A. P. <strong>Low frequency of p57(KIP2) mutation in Beckwith-Wiedemann syndrome.</strong> Am. J. Hum. Genet. 61: 304-309, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9311734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9311734</a>] [<a href="https://doi.org/10.1086/514858" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9311734">Lee et al. (1997)</a> analyzed the entire coding sequence and intron/exon boundaries of p57(KIP2) in 40 unrelated BWS patients. Only 2 (5%) showed mutations, both involving frameshifts in the second exon. In 1 case, the mutation was transmitted to the proband's mother, who was also affected, from the maternal grandfather, suggesting that this gene is not imprinted, at least in some affected tissues, at a critical stage of development and that haploinsufficiency due to mutation of either parental allele may cause at least some features of BWS. The low frequency of p57(KIP2) mutations, as well as the discovery of disruption of the LQT1 gene (see <a href="/entry/607542">607542</a>) in patients with chromosomal rearrangements, suggests that BWS can involve disruption of multiple independent genes on 11p15.5 <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9311734+9311733" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Hatada, I., Nabetani, A., Morisaki, H., Xin, Z., Ohishi, S., Tonoki, H., Niikawa, N., Inoue, M., Komoto, Y., Okada, A., Steichen, E., Ohashi, H., Fukushima, Y., Nakayama, M., Mukai, T. <strong>New p57(KIP2) mutations in Beckwith-Wiedemann syndrome.</strong> Hum. Genet. 100: 681-683, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9341892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9341892</a>] [<a href="https://doi.org/10.1007/s004390050573" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9341892">Hatada et al. (1997)</a> screened for mutations in the p57(KIP2) gene in 15 additional BWS patients and found 2 with mutations in this gene (e.g., <a href="#0003">600856.0003</a>). The rate of mutations was thus 4 in 24 cases, or 17%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9341892" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Lam, W. W. K., Hatada, I., Ohishi, S., Mukai, T., Joyce, J. A., Cole, T. R. P., Donnai, D., Reik, W., Schofield, P. N., Maher, E. R. <strong>Analysis of germline CDKN1C (p57-KIP2) mutations in familial and sporadic Beckwith-Wiedemann syndrome (BWS) provides a novel genotype-phenotype correlation.</strong> J. Med. Genet. 36: 518-523, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10424811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10424811</a>]" pmid="10424811">Lam et al. (1999)</a> sequenced the CDKN1C gene in 70 patients with BWS. Fifty-four were sporadic with no evidence of uniparental disomy and 16 were familial from 7 kindreds. Novel germline CDKN1C mutations were identified in 5 probands, 3 of 7 familial cases and 2 of 54 sporadic cases. There was no association between germline CDKN1C mutations and IGF2 or H19 abnormalities. There was a significantly higher frequency of exomphalos in the CDKN1C mutation cases as compared to cases with other types of molecular pathology. There was no association between germline CDKN1C mutations and risk of embryonal tumors. No CDKN1C mutations were identified in 6 non-BWS patients with overgrowth and Wilms tumor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10424811" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Algar, E. M., Deeble, G. J., Smith, P. J. <strong>CDKN1C expression in Beckwith-Wiedemann syndrome patients with allele imbalance.</strong> J. Med. Genet. 36: 524-531, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10424812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10424812</a>]" pmid="10424812">Algar et al. (1999)</a> reported 2 patients with mosaic paternal isodisomy of the 11p15 region. These patients had reduced levels of CDKN1C expression in the liver and kidney, respectively. Some expression from the paternally derived CDKN1C allele was evident, consistent with incomplete paternal imprinting. One patient showed maternal allele silencing, in addition to allele imbalance. <a href="#2" class="mim-tip-reference" title="Algar, E. M., Deeble, G. J., Smith, P. J. <strong>CDKN1C expression in Beckwith-Wiedemann syndrome patients with allele imbalance.</strong> J. Med. Genet. 36: 524-531, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10424812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10424812</a>]" pmid="10424812">Algar et al. (1999)</a> concluded that CDKN1C expression is reduced in patients with BWS with allele imbalance, and suggested that CDKN1C haploinsufficiency contributes to the BWS phenotype in patients with mosaic paternal isodisomy of chromosome 11. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10424812" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Algar, E., Brickell, S., Deeble, G., Amor, D., Smith, P. <strong>Analysis of CDKN1C in Beckwith Wiedemann syndrome.</strong> Hum. Mutat. 15: 497-508, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10862080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10862080</a>] [<a href="https://doi.org/10.1002/1098-1004(200006)15:6<497::AID-HUMU2>3.0.CO;2-F" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10862080">Algar et al. (2000)</a> examined 32 patients with BWS for mutations affecting the CDKN1C gene, including 7 cases of familial BWS. No mutations were detected in the coding region of the gene in any case; however, in 2 patients, 2 G-A base substitutions at adjacent positions in the 5-prime untranslated region were detected. These substitutions were also found in normal controls. In 3 of 18 cases studied by semiquantitative RT-PCR, CDKN1C expression was significantly reduced in the peripheral blood compared with controls. These and other results suggested that biallelic CDKN1C expression does not significantly perturb the overall levels of CDKN1C expression in somatic tissue. The results also confirmed other studies showing that the mechanisms associated with regulating CDKN1C expression and imprinting are separate from those regulating IGF2 imprinting. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10862080" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Romanelli, V., Belinchon, A., Benito-Sanz, S., Martinez-Glez, V., Gracia-Bouthelier, R., Heath, K. E., Campos-Barros, A., Garcia-Minaur, S., Fernandez, L., Meneses, H., Lopez-Siguero, J. P., Guillen-Navarro, E., and 9 others. <strong>CDKN1C (p57(Kip2)) analysis in Beckwith-Wiedemann syndrome (BWS) patients: Genotype-phenotype correlations, novel mutations, and polymorphisms.</strong> Am. J. Med. Genet. 152A: 1390-1397, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20503313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20503313</a>] [<a href="https://doi.org/10.1002/ajmg.a.33453" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20503313">Romanelli et al. (2010)</a> identified 7 novel mutations in the CDKN1C gene in 8 of 50 patients with BWS who did not have epigenetic alterations at chromosome 11q15. Six patients inherited the mutation from apparently asymptomatic mothers, 1 was de novo, and 1 could not be determined. Three of the mutations involved nucleotide 845 (see, e.g., <a href="#0004">600856.0004</a> and <a href="#0005">600856.0005</a>), suggesting a possible mutation hotspot. In additional to classic features of the disorder, 2 patients had polydactyly, 2 had an extra nipple, and 3 had cleft palate. No mutations were found in 22 patients with isolated hemihypertrophy, omphalocele, or macroglossia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20503313" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>IMAGE Syndrome</em></strong></p><p>
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In affected members of a 5-generation Argentinian family with intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies (IMAGE syndrome; <a href="/entry/614732">614732</a>) and 4 additional unrelated patients, <a href="#3" class="mim-tip-reference" title="Arboleda, V. A., Lee, H., Parnaik, R., Fleming, A., Banerjee, A., Ferraz-de-Souza, B., Delot, E. C., Rodriguez-Fernandez, I. A., Braslavsky, D., Bergada, I., Dell'Angelica, E. C., Nelson, S. F., Martinez-Agosto, J. A., Achermann, J. C., Vilain, E. <strong>Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome.</strong> Nature Genet. 44: 788-792, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22634751/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22634751</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22634751[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2275" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22634751">Arboleda et al. (2012)</a> identified heterozygous mutations in the CDKN1C gene (<a href="#0007">600856.0007</a>-<a href="#0011">600856.0011</a>). All 5 IMAGE-associated mutations are clustered in a highly conserved region of CDKN1C, near the PCNA (<a href="/entry/176740">176740</a>)-binding domain, and result in loss of PCNA binding. Targeted expression of IMAGE-associated CDKN1C mutations in Drosophila caused restricted eye and wing growth, suggesting a gain-of-function mechanism. Familial analysis showed an imprinted mode of inheritance in the Argentinian family, in which only maternal transmission of the mutation resulted in IMAGE syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22634751" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Association with Cancer</em></strong></p><p>
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<a href="#24" class="mim-tip-reference" title="Tokino, T., Urano, T., Furuhata, T., Matsushima, M., Miyatsu, T., Sasaki, S., Nakamura, Y. <strong>Characterization of the human p57(KIP2) gene: alternative splicing, insertion/deletion polymorphisms in VNTR sequences in the coding region, and mutational analysis.</strong> Hum. Genet. 97: 625-631, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8655143/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8655143</a>] [<a href="https://doi.org/10.1007/BF02281873" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8655143">Tokino et al. (1996)</a> examined the CDKN1C gene for genetic alterations in a large number of tumors. Although no somatic mutation was detected, they found several normal variations in this gene, including 4 types of 12-bp in-frame deletions in the proline/alanine repeating domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8655143" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Zhang, P., Leigeois, N. J., Wong, C., Finegold, M., Hou, H., Thompson, J. C., Silverman, A., Harper, J. W., DePinho, R. A., Elledge, S. J. <strong>Altered cell differentiation and proliferation in mice lacking p57(KIP2) indicates a role in Beckwith-Wiedemann syndrome.</strong> Nature 387: 151-158, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9144284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9144284</a>] [<a href="https://doi.org/10.1038/387151a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9144284">Zhang et al. (1997)</a> produced targeted disruption of the p57(KIP2) gene in mice and demonstrated that they have altered cell proliferation and differentiation, leading to abdominal muscle defects; cleft palate; endochondral bone ossification defects with incomplete differentiation of hypertrophic chondrocytes; renal medullary dysplasia; adrenal cortical hyperplasia and cytomegaly; and lens cell hyperproliferation and apoptosis. Since many of these phenotypes are observed in patients with BWS, <a href="#25" class="mim-tip-reference" title="Zhang, P., Leigeois, N. J., Wong, C., Finegold, M., Hou, H., Thompson, J. C., Silverman, A., Harper, J. W., DePinho, R. A., Elledge, S. J. <strong>Altered cell differentiation and proliferation in mice lacking p57(KIP2) indicates a role in Beckwith-Wiedemann syndrome.</strong> Nature 387: 151-158, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9144284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9144284</a>] [<a href="https://doi.org/10.1038/387151a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9144284">Zhang et al. (1997)</a> suggested that the observations support a loss of p57(KIP2) expression as having a role in that disorder. <a href="#25" class="mim-tip-reference" title="Zhang, P., Leigeois, N. J., Wong, C., Finegold, M., Hou, H., Thompson, J. C., Silverman, A., Harper, J. W., DePinho, R. A., Elledge, S. J. <strong>Altered cell differentiation and proliferation in mice lacking p57(KIP2) indicates a role in Beckwith-Wiedemann syndrome.</strong> Nature 387: 151-158, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9144284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9144284</a>] [<a href="https://doi.org/10.1038/387151a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9144284">Zhang et al. (1997)</a> noted that type X collagen (<a href="/entry/120110">120110</a>) is expressed in hypertrophic chondrocytes and has been implicated in proper bone development. In mutant mice, expression of type X collagen was significantly reduced in the mutant hypertrophic zone. Thus, the investigators concluded that p57(KIP2) is required for expression of collagen X, and perhaps other genes that facilitate the ossification of chondrocytes. Expression of p57(KIP2) is restricted to the fetal adrenal cortex and presumably plays a role in controlling cell proliferation; its absence leads to adrenal cortex hyperplasia and cytomegaly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9144284" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="John, R. M., Ainscough, J. F.-X., Barton, S. C., Surani, M. A. <strong>Distant cis-elements regulate imprinted expression of the mouse p57(Kip2) (Cdkn1c) gene: implications for the human disorder, Beckwith-Wiedemann syndrome.</strong> Hum. Molec. Genet. 10: 1601-1609, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11468278/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11468278</a>] [<a href="https://doi.org/10.1093/hmg/10.15.1601" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11468278">John et al. (2001)</a> used transgenic mice harboring modified BAC inserts to show that enhancers for expression (within skeletal muscle and cartilage) of the mouse p57Kip2 (Cdkn1c) gene were located at least 25 kb downstream. There was no evidence for allele-specific expression of Cdkn1c from BAC transgenes that spanned 315 kb around the locus. The authors suggested that a key imprinting element for Cdkn1c, as for IGF2, may lie at a distance, and hypothesized that Beckwith-Wiedemann syndrome in humans may result from disruption of appropriate expression of CDKN1C through mutations that occur at a substantial distance from the gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11468278" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>One-third of individuals with Beckwith-Wiedemann syndrome lose maternal-specific methylation at KvDMR1, a putative imprinting control region within intron 10 of the KCNQ1 gene (<a href="/entry/607542">607542</a>), and it has been proposed that this epimutation results in aberrant imprinting and, consequently, BWS. <a href="#9" class="mim-tip-reference" title="Fitzpatrick, G. V., Soloway, P. D., Higgins, M. J. <strong>Regional loss of imprinting and growth deficiency in mice with a targeted deletion of KvDMR1.</strong> Nature Genet. 32: 426-431, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12410230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12410230</a>] [<a href="https://doi.org/10.1038/ng988" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12410230">Fitzpatrick et al. (2002)</a> showed that paternal inheritance of this mutation in mice results in the derepression in cis of 6 genes, including Cdkn1c. Furthermore, fetuses and adult mice that inherited the deletion from their fathers were 20 to 25% smaller than their wildtype littermates. By contrast, maternal inheritance of this deletion had no effect on imprinted gene expression or growth. Thus, the unmethylated paternal KvDMR1 allele regulates imprinted expression by silencing genes on the paternal chromosome. These findings supported the hypothesis that loss of methylation in BWS patients activates the repressive function of KvDMR1 on the maternal chromosome, resulting in abnormal silencing of CDKN1C and the development of BWS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12410230" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs137852766 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852766;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=rs137852766" 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=rs137852766" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#13" class="mim-tip-reference" title="Hatada, I., Ohashi, H., Fukushima, Y., Kaneko, Y., Inoue, M., Komoto, Y., Okada, A., Ohishi, S., Nabetani, A., Morisaki, H., Nakayama, M., Niikawa, M,, Mukai, T. <strong>An imprinted gene p57(KIP2) is mutated in Beckwith-Wiedemann syndrome.</strong> Nature Genet. 14: 171-173, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8841187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8841187</a>] [<a href="https://doi.org/10.1038/ng1096-171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8841187">Hatada et al. (1996)</a> identified a heterozygous glu47-to-ter mutation in a 7-year-old boy with BWS (<a href="/entry/130650">130650</a>) caused by a C-to-T transition at nucleotide 399. They noted that this mutation would lead to a severely truncated polypeptide of 46 residues with disruption of the Cdk inhibitory domain and loss of the QT domain and the proline/alanine repeats. This mutation disrupts a PstI restriction site; digestion of the PCR-amplified DNA with PstI led to the identification of a novel 219-bp fragment in the patient in addition to 3 other fragments which were also detected in normal individuals. The parents, grandparents, and sister of the patient were healthy. PCR-amplified DNA from the parents was examined, and the mother was found to have the same 219-bp fragment that was present in the mutant allele of the patient. The father of the patient had only the normal allele. <a href="#13" class="mim-tip-reference" title="Hatada, I., Ohashi, H., Fukushima, Y., Kaneko, Y., Inoue, M., Komoto, Y., Okada, A., Ohishi, S., Nabetani, A., Morisaki, H., Nakayama, M., Niikawa, M,, Mukai, T. <strong>An imprinted gene p57(KIP2) is mutated in Beckwith-Wiedemann syndrome.</strong> Nature Genet. 14: 171-173, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8841187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8841187</a>] [<a href="https://doi.org/10.1038/ng1096-171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8841187">Hatada et al. (1996)</a> reported that the mother inherited the abnormal allele from her father. She was phenotypically normal, since p57(KIP2) is expressed from the maternal allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8841187" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 functional analysis of the glu47-to-ter mutation in the patient reported by <a href="#13" class="mim-tip-reference" title="Hatada, I., Ohashi, H., Fukushima, Y., Kaneko, Y., Inoue, M., Komoto, Y., Okada, A., Ohishi, S., Nabetani, A., Morisaki, H., Nakayama, M., Niikawa, M,, Mukai, T. <strong>An imprinted gene p57(KIP2) is mutated in Beckwith-Wiedemann syndrome.</strong> Nature Genet. 14: 171-173, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8841187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8841187</a>] [<a href="https://doi.org/10.1038/ng1096-171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8841187">Hatada et al. (1996)</a>, <a href="#5" class="mim-tip-reference" title="Bhuiyan, Z. A., Yatsuki, H., Sasaguri, T., Joh, K., Soejima, H., Zhu, X., Hatada, I. Morisaki, H., Morisaki, T., Mukai, T. <strong>Functional analysis of the p57(KIP2) gene mutation in Beckwith-Wiedemann syndrome.</strong> Hum. Genet. 104: 205-210, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10323243/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10323243</a>] [<a href="https://doi.org/10.1007/s004390050937" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10323243">Bhuiyan et al. (1999)</a> found that the mutation, which occurs in the Cdk inhibitory domain, renders the protein inactive with consequent complete loss of its role as a cell cycle inhibitor and of its nuclear localization. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8841187+10323243" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs2133780364 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2133780364;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=rs2133780364" 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=rs2133780364" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#13" class="mim-tip-reference" title="Hatada, I., Ohashi, H., Fukushima, Y., Kaneko, Y., Inoue, M., Komoto, Y., Okada, A., Ohishi, S., Nabetani, A., Morisaki, H., Nakayama, M., Niikawa, M,, Mukai, T. <strong>An imprinted gene p57(KIP2) is mutated in Beckwith-Wiedemann syndrome.</strong> Nature Genet. 14: 171-173, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8841187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8841187</a>] [<a href="https://doi.org/10.1038/ng1096-171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8841187">Hatada et al. (1996)</a> described a p57(KIP2) mutation in a 3-month-old girl with BWS (<a href="/entry/130650">130650</a>). This patient was heterozygous for a T-to-AG mutation at nucleotide 1086 that modified the 9 amino acids downstream, resulting in premature translation termination. The resultant 284-amino acid truncated polypeptide lacks the QT domain. The mutation disrupts an MboII restriction site in the gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8841187" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 functional analysis of this mutation in the patient reported by <a href="#13" class="mim-tip-reference" title="Hatada, I., Ohashi, H., Fukushima, Y., Kaneko, Y., Inoue, M., Komoto, Y., Okada, A., Ohishi, S., Nabetani, A., Morisaki, H., Nakayama, M., Niikawa, M,, Mukai, T. <strong>An imprinted gene p57(KIP2) is mutated in Beckwith-Wiedemann syndrome.</strong> Nature Genet. 14: 171-173, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8841187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8841187</a>] [<a href="https://doi.org/10.1038/ng1096-171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8841187">Hatada et al. (1996)</a>, <a href="#5" class="mim-tip-reference" title="Bhuiyan, Z. A., Yatsuki, H., Sasaguri, T., Joh, K., Soejima, H., Zhu, X., Hatada, I. Morisaki, H., Morisaki, T., Mukai, T. <strong>Functional analysis of the p57(KIP2) gene mutation in Beckwith-Wiedemann syndrome.</strong> Hum. Genet. 104: 205-210, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10323243/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10323243</a>] [<a href="https://doi.org/10.1007/s004390050937" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10323243">Bhuiyan et al. (1999)</a> found that the mutant protein, although completely retaining its cell cycle regulatory activity, lacks nuclear localization, and is thus prevented from performing its role as an active cell cycle inhibitor. The mutant allele was inherited from the mother, as was the case with the glu47-to-ter mutation (<a href="#0001">600856.0001</a>) described by <a href="#13" class="mim-tip-reference" title="Hatada, I., Ohashi, H., Fukushima, Y., Kaneko, Y., Inoue, M., Komoto, Y., Okada, A., Ohishi, S., Nabetani, A., Morisaki, H., Nakayama, M., Niikawa, M,, Mukai, T. <strong>An imprinted gene p57(KIP2) is mutated in Beckwith-Wiedemann syndrome.</strong> Nature Genet. 14: 171-173, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8841187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8841187</a>] [<a href="https://doi.org/10.1038/ng1096-171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8841187">Hatada et al. (1996)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8841187+10323243" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs387906399 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906399;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=rs387906399" 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=rs387906399" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a familial case of BWS (<a href="/entry/130650">130650</a>), <a href="#12" class="mim-tip-reference" title="Hatada, I., Nabetani, A., Morisaki, H., Xin, Z., Ohishi, S., Tonoki, H., Niikawa, N., Inoue, M., Komoto, Y., Okada, A., Steichen, E., Ohashi, H., Fukushima, Y., Nakayama, M., Mukai, T. <strong>New p57(KIP2) mutations in Beckwith-Wiedemann syndrome.</strong> Hum. Genet. 100: 681-683, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9341892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9341892</a>] [<a href="https://doi.org/10.1007/s004390050573" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9341892">Hatada et al. (1997)</a> found a heterozygous CT-to-G transversion/deletion at nucleotide 570 of CDKN1C, leading to a frameshift at codon 104 resulting in the loss of the QT domain and the PAPA repeats of the gene product. The patient's father was normal but his mother had gigantism during infancy. The patient's sister also had BWS and showed the same mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9341892" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs104894200 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894200;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=rs104894200" 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=rs104894200" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient with BWS (<a href="/entry/130650">130650</a>), <a href="#12" class="mim-tip-reference" title="Hatada, I., Nabetani, A., Morisaki, H., Xin, Z., Ohishi, S., Tonoki, H., Niikawa, N., Inoue, M., Komoto, Y., Okada, A., Steichen, E., Ohashi, H., Fukushima, Y., Nakayama, M., Mukai, T. <strong>New p57(KIP2) mutations in Beckwith-Wiedemann syndrome.</strong> Hum. Genet. 100: 681-683, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9341892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9341892</a>] [<a href="https://doi.org/10.1007/s004390050573" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9341892">Hatada et al. (1997)</a> found heterozygosity for a C-to-A transversion at nucleotide 1000 of the CDKN1C gene, changing ser247 (TCG) to a termination (TAG) codon. This resulted in a truncated polypeptide of 246 residues with a disruption of the QT domain. The mutation pointed to an important role of the QT domain in growth regulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9341892" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs267606716 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606716;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=rs267606716" 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=rs267606716" 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=RCV000009291 OR RCV000521869" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009291, RCV000521869" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009291...</a>
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<p>In a 32-year-old man with BWS (<a href="/entry/130650">130650</a>), <a href="#21" class="mim-tip-reference" title="Romanelli, V., Belinchon, A., Benito-Sanz, S., Martinez-Glez, V., Gracia-Bouthelier, R., Heath, K. E., Campos-Barros, A., Garcia-Minaur, S., Fernandez, L., Meneses, H., Lopez-Siguero, J. P., Guillen-Navarro, E., and 9 others. <strong>CDKN1C (p57(Kip2)) analysis in Beckwith-Wiedemann syndrome (BWS) patients: Genotype-phenotype correlations, novel mutations, and polymorphisms.</strong> Am. J. Med. Genet. 152A: 1390-1397, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20503313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20503313</a>] [<a href="https://doi.org/10.1002/ajmg.a.33453" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20503313">Romanelli et al. (2010)</a> identified a heterozygous 845C-G transversion in the CDKN1C gene, resulting in a ser282-to-ter (S282X) substitution in domain III. He had generalized overgrowth, macroglossia, ear creases, and omphalocele. Other features included cryptorchidism and hypoglycemia. The mutation resulted in the same amino acid change as that found in another patient (845C-A; <a href="#0006">600856.0006</a>), suggesting a possible hotspot at this nucleotide. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20503313" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs267606716 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606716;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=rs267606716" 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=rs267606716" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 7-year-old boy with BWS (<a href="/entry/130650">130650</a>), <a href="#21" class="mim-tip-reference" title="Romanelli, V., Belinchon, A., Benito-Sanz, S., Martinez-Glez, V., Gracia-Bouthelier, R., Heath, K. E., Campos-Barros, A., Garcia-Minaur, S., Fernandez, L., Meneses, H., Lopez-Siguero, J. P., Guillen-Navarro, E., and 9 others. <strong>CDKN1C (p57(Kip2)) analysis in Beckwith-Wiedemann syndrome (BWS) patients: Genotype-phenotype correlations, novel mutations, and polymorphisms.</strong> Am. J. Med. Genet. 152A: 1390-1397, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20503313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20503313</a>] [<a href="https://doi.org/10.1002/ajmg.a.33453" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20503313">Romanelli et al. (2010)</a> identified a heterozygous 845C-A transversion in the CDKN1C gene, resulting in a ser282-to-ter (S282X) substitution in domain III. He had generalized overgrowth, macroglossia, ear creases, and omphalocele. Additional features included cleft palate and an extra nipple. The mutation resulted in the same amino acid change as that found in another patient (845C-G; <a href="#0005">600856.0005</a>), suggesting a possible hotspot at this nucleotide. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20503313" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0007 INTRAUTERINE GROWTH RETARDATION, METAPHYSEAL DYSPLASIA, ADRENAL HYPOPLASIA CONGENITA, AND GENITAL ANOMALIES</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">rs387907223 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907223;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=rs387907223" 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=rs387907223" 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=RCV004814925" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV004814925" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV004814925</a>
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<p>In 7 affected members of a 5-generation Argentinian family with intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies (IMAGE syndrome; <a href="/entry/614732">614732</a>), originally reported by <a href="#4" class="mim-tip-reference" title="Bergada, I., del Rey, G., Lapunzina, P., Bergada, C., Fellous, M., Copelli, S. <strong>Familial occurrence of the IMAGe association: additional clinical variants and a proposed mode of inheritance.</strong> J. Clin. Endocr. Metab. 90: 3186-3190, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15769992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15769992</a>] [<a href="https://doi.org/10.1210/jc.2004-1589" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15769992">Bergada et al. (2005)</a>, <a href="#3" class="mim-tip-reference" title="Arboleda, V. A., Lee, H., Parnaik, R., Fleming, A., Banerjee, A., Ferraz-de-Souza, B., Delot, E. C., Rodriguez-Fernandez, I. A., Braslavsky, D., Bergada, I., Dell'Angelica, E. C., Nelson, S. F., Martinez-Agosto, J. A., Achermann, J. C., Vilain, E. <strong>Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome.</strong> Nature Genet. 44: 788-792, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22634751/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22634751</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22634751[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2275" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22634751">Arboleda et al. (2012)</a> identified heterozygosity for an 825T-G transversion in the CDKN1C gene, resulting in a phe276-to-val (F276V) substitution at a highly conserved residue near the PCNA (<a href="/entry/176740">176740</a>)-binding domain. The variant was not present in the dbSNP (build 129) database. Inheritance of IMAGE syndrome was only through maternal transmission of the F276V mutation: sequencing in 24 family members confirmed that only individuals who inherited the 825T-G mutation on the maternal allele were affected, presumably due to epigenetic silencing of the mutated allele when it occurred on the paternal allele. Analysis of transfected HEK293 cells suggested disruption of PCNA binding. Overexpression of the F276V mutant in Drosophila resulted in moderate restriction of wing and eye growth, suggestive of a gain-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15769992+22634751" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 INTRAUTERINE GROWTH RETARDATION, METAPHYSEAL DYSPLASIA, ADRENAL HYPOPLASIA CONGENITA, AND GENITAL ANOMALIES</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">rs387907224 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907224;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=rs387907224" 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=rs387907224" 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=RCV001596942 OR RCV004814926" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001596942, RCV004814926" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001596942...</a>
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<p>In a patient with intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies (IMAGE syndrome; <a href="/entry/614732">614732</a>), <a href="#3" class="mim-tip-reference" title="Arboleda, V. A., Lee, H., Parnaik, R., Fleming, A., Banerjee, A., Ferraz-de-Souza, B., Delot, E. C., Rodriguez-Fernandez, I. A., Braslavsky, D., Bergada, I., Dell'Angelica, E. C., Nelson, S. F., Martinez-Agosto, J. A., Achermann, J. C., Vilain, E. <strong>Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome.</strong> Nature Genet. 44: 788-792, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22634751/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22634751</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22634751[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2275" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22634751">Arboleda et al. (2012)</a> identified heterozygosity for an 826T-C transition in the CDKN1C gene, resulting in a phe276-to-ser (F276S) substitution at a highly conserved residue near the PCNA (<a href="/entry/176740">176740</a>)-binding domain. The variant was not present in the dbSNP (build 129) database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22634751" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 INTRAUTERINE GROWTH RETARDATION, METAPHYSEAL DYSPLASIA, ADRENAL HYPOPLASIA CONGENITA, AND GENITAL ANOMALIES</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">rs318240750 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs318240750;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=rs318240750" 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=rs318240750" 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=RCV004814927" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV004814927" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV004814927</a>
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<p>In a patient with intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies (IMAGE syndrome; <a href="/entry/614732">614732</a>), <a href="#3" class="mim-tip-reference" title="Arboleda, V. A., Lee, H., Parnaik, R., Fleming, A., Banerjee, A., Ferraz-de-Souza, B., Delot, E. C., Rodriguez-Fernandez, I. A., Braslavsky, D., Bergada, I., Dell'Angelica, E. C., Nelson, S. F., Martinez-Agosto, J. A., Achermann, J. C., Vilain, E. <strong>Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome.</strong> Nature Genet. 44: 788-792, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22634751/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22634751</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22634751[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2275" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22634751">Arboleda et al. (2012)</a> identified heterozygosity for an 835G-C transversion in the CDKN1C gene, resulting in an arg279-to-pro (R279P) substitution at a highly conserved residue near the PCNA (<a href="/entry/176740">176740</a>)-binding domain. The variant was not present in the dbSNP (build 129) database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22634751" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 INTRAUTERINE GROWTH RETARDATION, METAPHYSEAL DYSPLASIA, ADRENAL HYPOPLASIA CONGENITA, AND GENITAL ANOMALIES</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">rs387907225 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907225;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=rs387907225" 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=rs387907225" 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=RCV001380060 OR RCV002513231 OR RCV004814928" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001380060, RCV002513231, RCV004814928" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001380060...</a>
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<p>In a patient with intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies (IMAGE syndrome; <a href="/entry/614732">614732</a>), <a href="#3" class="mim-tip-reference" title="Arboleda, V. A., Lee, H., Parnaik, R., Fleming, A., Banerjee, A., Ferraz-de-Souza, B., Delot, E. C., Rodriguez-Fernandez, I. A., Braslavsky, D., Bergada, I., Dell'Angelica, E. C., Nelson, S. F., Martinez-Agosto, J. A., Achermann, J. C., Vilain, E. <strong>Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome.</strong> Nature Genet. 44: 788-792, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22634751/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22634751</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22634751[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2275" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22634751">Arboleda et al. (2012)</a> identified heterozygosity for an 819G-A transition in the CDKN1C gene, resulting in an asp274-to-asn (D274N) substitution at a highly conserved residue near the PCNA (<a href="/entry/176740">176740</a>)-binding domain. The variant was not present in the dbSNP (build 129) database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22634751" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 INTRAUTERINE GROWTH RETARDATION, METAPHYSEAL DYSPLASIA, ADRENAL HYPOPLASIA CONGENITA, AND GENITAL ANOMALIES</strong>
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CDKN1C, LYS278GLU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387907226 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907226;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=rs387907226" 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=rs387907226" 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=RCV004814929" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV004814929" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV004814929</a>
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<p>In a patient with intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies (IMAGE syndrome; <a href="/entry/614732">614732</a>), <a href="#3" class="mim-tip-reference" title="Arboleda, V. A., Lee, H., Parnaik, R., Fleming, A., Banerjee, A., Ferraz-de-Souza, B., Delot, E. C., Rodriguez-Fernandez, I. A., Braslavsky, D., Bergada, I., Dell'Angelica, E. C., Nelson, S. F., Martinez-Agosto, J. A., Achermann, J. C., Vilain, E. <strong>Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome.</strong> Nature Genet. 44: 788-792, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22634751/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22634751</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22634751[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2275" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22634751">Arboleda et al. (2012)</a> identified heterozygosity for an 831A-G transition in the CDKN1C gene, resulting in a lys278-to-glu (K278E) substitution at a highly conserved residue near the PCNA (<a href="/entry/176740">176740</a>)-binding domain. The variant was not present in the dbSNP (build 129) database. Analysis of transfected HEK293 cells suggested disruption of PCNA binding. Overexpression of the K278E mutant in Drosophila resulted in moderate restriction of wing and eye growth, suggestive of a gain-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22634751" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>REFERENCES</strong>
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Algar, E., Brickell, S., Deeble, G., Amor, D., Smith, P.
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[<a href="https://doi.org/10.1002/1098-1004(200006)15:6<497::AID-HUMU2>3.0.CO;2-F" target="_blank">Full Text</a>]
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Algar, E. M., Deeble, G. J., Smith, P. J.
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<strong>CDKN1C expression in Beckwith-Wiedemann syndrome patients with allele imbalance.</strong>
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Arboleda, V. A., Lee, H., Parnaik, R., Fleming, A., Banerjee, A., Ferraz-de-Souza, B., Delot, E. C., Rodriguez-Fernandez, I. A., Braslavsky, D., Bergada, I., Dell'Angelica, E. C., Nelson, S. F., Martinez-Agosto, J. A., Achermann, J. C., Vilain, E.
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<strong>Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome.</strong>
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Nature Genet. 44: 788-792, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22634751/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22634751</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22634751[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=22634751" 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/ng.2275" target="_blank">Full Text</a>]
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Bergada, I., del Rey, G., Lapunzina, P., Bergada, C., Fellous, M., Copelli, S.
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<strong>Familial occurrence of the IMAGe association: additional clinical variants and a proposed mode of inheritance.</strong>
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J. Clin. Endocr. Metab. 90: 3186-3190, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15769992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15769992</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15769992" 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/10.1210/jc.2004-1589" target="_blank">Full Text</a>]
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Bhuiyan, Z. A., Yatsuki, H., Sasaguri, T., Joh, K., Soejima, H., Zhu, X., Hatada, I. Morisaki, H., Morisaki, T., Mukai, T.
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<strong>Functional analysis of the p57(KIP2) gene mutation in Beckwith-Wiedemann syndrome.</strong>
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Hum. Genet. 104: 205-210, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10323243/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10323243</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10323243" 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/10.1007/s004390050937" target="_blank">Full Text</a>]
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Diaz-Meyer, N., Yang, Y., Sait, S. N., Maher, E. R., Higgins, M. J.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16061564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16061564</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16061564" 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.2004.030593" target="_blank">Full Text</a>]
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Du, M., Beatty, L. G., Zhou, W., Lew, J., Schoenherr, C., Weksberg, R., Sadowski, P. D.
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<strong>Insulator and silencer sequences in the imprinted region of human chromosome 11p15.5.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12874112/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12874112</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12874112" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddg194" target="_blank">Full Text</a>]
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Fisher, R. A., Hodges, M. D., Rees, H. C., Sebire, N. J., Seckl, M. J., Newlands, E. S., Genest, D. R., Castrillon, D. H.
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<strong>The maternally transcribed gene p57(KIP2) (CDNK1C) is abnormally expressed in both androgenetic and biparental complete hydatidiform moles.</strong>
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[<a href="https://doi.org/10.1038/ng988" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature09130" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550351</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7550351" 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/ng1095-204" target="_blank">Full Text</a>]
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<a id="Hatada1997" class="mim-anchor"></a>
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<div class="">
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Hatada, I., Nabetani, A., Morisaki, H., Xin, Z., Ohishi, S., Tonoki, H., Niikawa, N., Inoue, M., Komoto, Y., Okada, A., Steichen, E., Ohashi, H., Fukushima, Y., Nakayama, M., Mukai, T.
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<strong>New p57(KIP2) mutations in Beckwith-Wiedemann syndrome.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9341892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9341892</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9341892" 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/10.1007/s004390050573" target="_blank">Full Text</a>]
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Hatada, I., Ohashi, H., Fukushima, Y., Kaneko, Y., Inoue, M., Komoto, Y., Okada, A., Ohishi, S., Nabetani, A., Morisaki, H., Nakayama, M., Niikawa, M,, Mukai, T.
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<strong>An imprinted gene p57(KIP2) is mutated in Beckwith-Wiedemann syndrome.</strong>
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[<a href="https://doi.org/10.1038/ng1096-171" target="_blank">Full Text</a>]
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<a id="John2001" class="mim-anchor"></a>
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<strong>Distant cis-elements regulate imprinted expression of the mouse p57(Kip2) (Cdkn1c) gene: implications for the human disorder, Beckwith-Wiedemann syndrome.</strong>
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[<a href="https://doi.org/10.1093/hmg/10.15.1601" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9311734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9311734</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9311734" 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/10.1086/514858" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1101/gad.9.6.639" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1101/gad.9.6.650" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8610162/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8610162</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8610162" 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.93.7.3026" target="_blank">Full Text</a>]
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<strong>Coding mutations in p57(KIP2) are present in some cases of Beckwith-Wiedemann syndrome but are rare or absent in Wilms tumors.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9311733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9311733</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9311733" 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/10.1086/514854" target="_blank">Full Text</a>]
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<a id="Romanelli2010" class="mim-anchor"></a>
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Romanelli, V., Belinchon, A., Benito-Sanz, S., Martinez-Glez, V., Gracia-Bouthelier, R., Heath, K. E., Campos-Barros, A., Garcia-Minaur, S., Fernandez, L., Meneses, H., Lopez-Siguero, J. P., Guillen-Navarro, E., and 9 others.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20503313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20503313</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20503313" 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.33453" target="_blank">Full Text</a>]
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<a id="Scandura2004" class="mim-anchor"></a>
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<strong>Transforming growth factor beta-induced cell cycle arrest of human hematopoietic cells requires p57KIP2 upregulation.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15477587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15477587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15477587[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=15477587" 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.0406771101" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0508035103" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF02281873" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9144284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9144284</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9144284" 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/10.1038/387151a0" 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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Marla J. F. O'Neill - updated : 7/20/2012
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Cassandra L. Kniffin - updated : 11/29/2010<br>Ada Hamosh - updated : 9/27/2010<br>Anne M. Stumpf - updated : 8/4/2006<br>Ada Hamosh - updated : 8/4/2006<br>Marla J. F. O'Neill - updated : 9/13/2005<br>George E. Tiller - updated : 5/9/2005<br>Patricia A. Hartz - updated : 11/16/2004<br>George E. Tiller - updated : 9/13/2004<br>Victor A. McKusick - updated : 9/13/2002<br>George E. Tiller - updated : 12/18/2001<br>Victor A. McKusick - updated : 6/30/2000<br>Michael J. Wright - updated : 8/16/1999<br>Victor A. McKusick - updated : 4/23/1999<br>Victor A. McKusick - updated : 10/7/1997<br>Victor A. McKusick - updated : 9/24/1997<br>Victor A. McKusick - updated : 5/9/1997<br>Moyra Smith - updated : 10/2/1996
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Victor A. McKusick : 10/11/1995
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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carol : 04/07/2017
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alopez : 10/17/2016<br>alopez : 01/29/2014<br>mgross : 2/5/2013<br>carol : 7/20/2012<br>terry : 5/24/2012<br>mgross : 8/9/2011<br>wwang : 12/1/2010<br>ckniffin : 11/29/2010<br>alopez : 9/28/2010<br>terry : 9/27/2010<br>alopez : 9/7/2006<br>alopez : 8/4/2006<br>alopez : 8/4/2006<br>carol : 9/13/2005<br>terry : 9/13/2005<br>terry : 9/13/2005<br>tkritzer : 5/9/2005<br>mgross : 11/16/2004<br>tkritzer : 9/20/2004<br>tkritzer : 9/13/2004<br>ckniffin : 2/5/2003<br>alopez : 11/4/2002<br>alopez : 9/16/2002<br>carol : 9/13/2002<br>cwells : 12/28/2001<br>cwells : 12/18/2001<br>mcapotos : 7/17/2000<br>mcapotos : 7/13/2000<br>terry : 6/30/2000<br>alopez : 8/18/1999<br>alopez : 8/18/1999<br>terry : 8/16/1999<br>mgross : 5/6/1999<br>mgross : 4/27/1999<br>terry : 4/23/1999<br>terry : 6/4/1998<br>mark : 10/14/1997<br>terry : 10/7/1997<br>terry : 9/30/1997<br>terry : 9/24/1997<br>mark : 8/12/1997<br>mark : 5/9/1997<br>mark : 5/7/1997<br>terry : 1/17/1997<br>jamie : 10/23/1996<br>jamie : 10/18/1996<br>mark : 10/5/1996<br>mark : 10/4/1996<br>mark : 10/2/1996<br>mark : 10/2/1996<br>mark : 4/19/1996<br>terry : 4/17/1996<br>mark : 4/16/1996<br>terry : 4/9/1996<br>mark : 12/13/1995<br>terry : 10/30/1995<br>mark : 10/11/1995
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<span class="mim-font">
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<strong>*</strong> 600856
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<h3>
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CYCLIN-DEPENDENT KINASE INHIBITOR 1C; CDKN1C
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<span class="mim-font">
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p57(KIP2)<br />
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KIP2
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<strong><em>HGNC Approved Gene Symbol: CDKN1C</em></strong>
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<strong>SNOMEDCT:</strong> 702384004, 81780002;
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<strong>ICD10CM:</strong> Q87.3;
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<strong>
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Cytogenetic location: 11p15.4
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Genomic coordinates <span class="small">(GRCh38)</span> : 11:2,883,218-2,885,775 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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11p15.4
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Beckwith-Wiedemann syndrome
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<span class="mim-font">
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130650
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Autosomal dominant
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<span class="mim-font">
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3
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IMAGE syndrome
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<span class="mim-font">
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614732
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<span class="mim-font">
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Autosomal dominant
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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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<strong>TEXT</strong>
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<span class="mim-font">
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<strong>Description</strong>
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<p>The CDKN1C gene encodes p57(KIP2), a potent tight-binding inhibitor of several G1 cyclin/Cdk complexes and a negative regulator of cell proliferation (Lee et al., 1995). The CDKN1C gene is paternally imprinted, with preferential expression of the maternal allele (Hatada and Mukai, 1995). </p>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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<p>Lee et al. (1995) and Matsuoka et al. (1995) reported that the human p57(KIP2) gene encodes a 316-amino acid protein consisting of 3 structurally distinct domains, including an N-terminal CDK inhibitory domain with significant similarity to p21(CIP1) (116899). </p><p>By quantitative RT-PCR, Arboleda et al. (2012) demonstrated that expression of CDKN1C is greater in adrenal tissue than in brain or muscle during early human development. Immunohistochemistry showed the strongest expression of CDKN1C within a subset of cells in the subcapsular or developing definitive zone of the adrenal gland. </p>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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<span class="mim-text-font">
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<p>The CDKN1C gene contains 3 exons (Tokino et al., 1996). </p>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</div>
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<span class="mim-text-font">
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<p>Matsuoka et al. (1995) demonstrated that the CDKN1C gene is located on chromosome 11p15.5, a region implicated in both sporadic cancers and Beckwith-Wiedemann syndrome, a familial cancer syndrome, making it a tumor suppressor candidate. Several types of childhood tumors, including Wilms tumor (194071), adrenocortical carcinoma (202300), and rhabdomyosarcoma (268210), display a specific loss of maternal 11p15 alleles, suggesting that genomic imprinting plays an important role. </p>
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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 class="mim-text-font">
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<p>Hatada and Mukai (1995) showed that a mouse homolog of p57(KIP2) is genomically imprinted. The paternally inherited allele is transcriptionally repressed and methylated. The mouse gene maps to the distal region of chromosome 7, within a cluster of imprinted genes, including insulin-like growth factor-2 (IGF2; 147470) and H19 (103280). Matsuoka et al. (1996) demonstrated that the p57(KIP2) gene is imprinted in the human also. It is situated 500 kb centromeric to the IGF2 gene. The maternal allele is preferentially expressed; however, the imprint is not absolute, as the paternal allele is also expressed at low levels in most tissues and at levels comparable to the maternal allele in fetal brain and some embryonal tumors. It appears to lie in a domain containing other imprinted genes. Matsuoka et al. (1996) commented that establishment of an imprint may be coordinately regulated throughout the entire domain, as suggested by similar tissue-specific expression and imprinting patterns of IGF2, H19, and p57(KIP2) genes, while loss of imprinting (LOI) may not necessarily affect the entire region. </p><p>Du et al. (2003) confirmed the existence of insulators in the differentially methylated region (DMR) of the H19 gene and reported 2 insulators in the IGF2 gene. They also found 2 novel silencer sequences: 1 in KvDMR, a region that is thought to contain the promoter for the KCNQ1OT1 (604115) transcript, and the other in CDKN1C. The authors demonstrated binding of the zinc finger protein CTCF (604167) in vitro to all the insulator and silencer sequences detected. </p><p>Using primary human hematopoietic cells and microarray analysis, Scandura et al. (2004) identified p57(KIP2) as the only cyclin-dependent kinase inhibitor induced by TGF-beta (190180). Upregulation of p57 mRNA and protein occurred before TGF-beta-induced G1 cell cycle arrest, required transcription, and was mediated via a highly conserved region of the proximal p57 promoter. Upregulation of p57 was essential for TGF-beta-induced cell cycle arrest in these cells, since 2 different small interfering RNAs that prevented p57 upregulation blocked the cytostatic effects of TGF-beta on the hematopoietic cells. </p><p>In DNA from Beckwith-Wiedemann syndrome (BWS; 130650) patients with downregulated CDKN1C and normal methylation at KvDMR1, Diaz-Meyer et al. (2005) observed depletion of dimethylated H3-K4 (see 602810) and enrichment of dimethylated H3-K9 and HP1-gamma (604477) at the CDKN1C promoter, suggesting that in these cases gene silencing is associated with repressive chromatin changes. Diaz-Meyer et al. (2005) concluded that CDKN1C may be downregulated by multiple mechanisms including some that do not involve promoter methylation. </p><p>Using DNA microarrays to compare gene expression patterns in normal human placenta with those in other tissues, Sood et al. (2006) found that several genes involved in growth and tissue remodeling were expressed at relatively higher levels in the villus sections of placenta compared with other tissues. These included GPC3 (300037), CDKN1C, and IGF2. The GPC3 and CDKN1C genes are mutated in patients with Simpson-Golabi-Behmel syndrome (312870) and BWS, respectively, both fetal-placental overgrowth syndromes. In contrast, loss of IGF2 is associated with fetal growth restriction in mice. The relatively higher expression of genes that both promote and suppress growth suggested to Sood et al. (2006) tight and local regulation of the pathways that control placental development. </p><p>In mice, adult cardiomyocytes primarily express alpha-myosin heavy chain (alpha-MHC, also known as Myh6; 160710), whereas embryonic cardiomyocytes express beta-MHC (also known as Myh7; 160760). Cardiac stress triggers adult hearts to undergo hypertrophy and a shift from alpha-MHC to fetal beta-MHC expression. Hang et al. (2010) showed that BRG1 (603254), a chromatin-remodeling protein, has a critical role in regulating cardiac growth, differentiation, and gene expression. In embryos, Brg1 promotes myocyte proliferation by maintaining Bmp10 (608748) and suppressing p57(kip2) expression. It preserves fetal cardiac differentiation by interacting with histone deacetylases (HDACs; see 601241) and poly(ADP ribose) polymerase (PARP; 173870) to repress alpha-MHC and activate beta-MHC. In adults, Brg1 (also known as Smarca4) is turned off in cardiomyocytes. It is reactivated by cardiac stresses and forms a complex with its embryonic partners, HDAC and PARP, to induce a pathologic alpha-MHC-to-beta-MHC shift. Preventing Brg1 reexpression decreases hypertrophy and reverses this MHC switch. BRG1 is activated in certain patients with hypertrophic cardiomyopathy, its level correlating with disease severity and MHC changes. Hang et al. (2010) concluded that their studies showed that BRG1 maintains cardiomyocytes in an embryonic state, and demonstrated an epigenetic mechanism by which 3 classes of chromatin-modifying factors, BRG1, HDAC, and PARP, cooperate to control developmental and pathologic gene expression. </p>
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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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</div>
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<span class="mim-text-font">
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<p>Hydatidiform mole (HYDM; 231090) is an abnormal gestation characterized by trophoblast hyperplasia and overgrowth of placental villi. The genetic basis in the vast majority of cases is an excess of paternal to maternal genomes, suggesting that global misexpression of imprinted genes is the common underlying molecular mechanism. Although most cases of complete HYDM are androgenetic in origin, a rare, frequently familial, biparental variant has been described. In a series of patients with biparental complete HYDM, Fisher et al. (2002) observed dramatic underexpression of CDKN1C identical to the pattern seen in complete HYDM of androgenetic origin. The series included 2 sisters, both of whom had biparental complete HYDM. Genotyping of this family identified a 15-cM region of homozygosity for 19q13.3-q13.4 similar to that found in 3 other families with recurrent biparental complete HYDM. Fisher et al. (2002) concluded that biparental complete HYDM, like complete HYDM of androgenetic origin, may result from abnormal expression of imprinted genes (such as CDKN1C), and that a locus on 19q13.3-q13.4 may regulate expression of imprinted genes on other chromosomes. </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>Molecular Genetics</strong>
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</span>
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<span class="mim-text-font">
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<p><strong><em>Beckwith-Wiedemann Syndrome</em></strong></p><p>
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Hatada et al. (1996) studied the p57(KIP2) gene in DNA samples from 9 unrelated Japanese patients with Beckwith-Wiedemann syndrome. They detected mutations in 2 BWS patients. In a 7-year-old boy with Beckwith Wiedemann syndrome (diagnosed on the basis of increased birth weight, omphalocele, macroglossia, intractable neonatal hypoglycemia, facial nevus flammeus, and earlobe grooves), PCR amplification and direct sequencing analysis led to identification of a heterozygous C-to-T transition at nucleotide 399, changing glutamine (CAG) to a termination codon (TAG) at position 47 (600856.0001). The mother was also heterozygous for the mutation but had inherited it from her father. She was phenotypically normal, since p57(KIP2) is expressed from the maternal allele (which was normal in her case). Hatada et al. (1996) also described a p57(KIP2) mutation in a 3-month-old girl with BWS. This patient was heterozygous for a T-to-AG change at nucleotide 1086 that modified the 9 amino acids downstream and resulted in a premature translation termination (600856.0002). In one other patient Hatada et al. (1996) demonstrated reduced expression of the p57(KIP2) gene in adrenal gland. Hatada et al. (1996) concluded that their studies provided evidence for a new mechanism for producing a phenotype with dominant transmission with little or no gene product: one allele with an inactive product is expressed and the other allele is repressed by genomic imprinting. Hatada et al. (1996) commented that other loci may possibly be involved in BWS since there are 3 other known balanced translocations leading to BWS which map several megabases from the p57(KIP2) region. </p><p>By complete sequencing of the coding exons and intron/exon junctions of the CDKN1C gene, O'Keefe et al. (1997) found a maternally transmitted coding mutation in the CDK-inhibitor domain of the KIP2 gene in 1 of 5 cases of BWS. The mutation was an in-frame 3-amino acid deletion that significantly reduced but did not fully abrogate growth-suppressive activity in transfection assay. In contrast, no somatic coding mutations from KIP2 were found in a set of 12 primary Wilms tumors enriched for cases that expressed KIP2 mRNA, including cases with and without 11p15.5 loss of heterozygosity. Lee et al. (1997) analyzed the entire coding sequence and intron/exon boundaries of p57(KIP2) in 40 unrelated BWS patients. Only 2 (5%) showed mutations, both involving frameshifts in the second exon. In 1 case, the mutation was transmitted to the proband's mother, who was also affected, from the maternal grandfather, suggesting that this gene is not imprinted, at least in some affected tissues, at a critical stage of development and that haploinsufficiency due to mutation of either parental allele may cause at least some features of BWS. The low frequency of p57(KIP2) mutations, as well as the discovery of disruption of the LQT1 gene (see 607542) in patients with chromosomal rearrangements, suggests that BWS can involve disruption of multiple independent genes on 11p15.5 </p><p>Hatada et al. (1997) screened for mutations in the p57(KIP2) gene in 15 additional BWS patients and found 2 with mutations in this gene (e.g., 600856.0003). The rate of mutations was thus 4 in 24 cases, or 17%. </p><p>Lam et al. (1999) sequenced the CDKN1C gene in 70 patients with BWS. Fifty-four were sporadic with no evidence of uniparental disomy and 16 were familial from 7 kindreds. Novel germline CDKN1C mutations were identified in 5 probands, 3 of 7 familial cases and 2 of 54 sporadic cases. There was no association between germline CDKN1C mutations and IGF2 or H19 abnormalities. There was a significantly higher frequency of exomphalos in the CDKN1C mutation cases as compared to cases with other types of molecular pathology. There was no association between germline CDKN1C mutations and risk of embryonal tumors. No CDKN1C mutations were identified in 6 non-BWS patients with overgrowth and Wilms tumor. </p><p>Algar et al. (1999) reported 2 patients with mosaic paternal isodisomy of the 11p15 region. These patients had reduced levels of CDKN1C expression in the liver and kidney, respectively. Some expression from the paternally derived CDKN1C allele was evident, consistent with incomplete paternal imprinting. One patient showed maternal allele silencing, in addition to allele imbalance. Algar et al. (1999) concluded that CDKN1C expression is reduced in patients with BWS with allele imbalance, and suggested that CDKN1C haploinsufficiency contributes to the BWS phenotype in patients with mosaic paternal isodisomy of chromosome 11. </p><p>Algar et al. (2000) examined 32 patients with BWS for mutations affecting the CDKN1C gene, including 7 cases of familial BWS. No mutations were detected in the coding region of the gene in any case; however, in 2 patients, 2 G-A base substitutions at adjacent positions in the 5-prime untranslated region were detected. These substitutions were also found in normal controls. In 3 of 18 cases studied by semiquantitative RT-PCR, CDKN1C expression was significantly reduced in the peripheral blood compared with controls. These and other results suggested that biallelic CDKN1C expression does not significantly perturb the overall levels of CDKN1C expression in somatic tissue. The results also confirmed other studies showing that the mechanisms associated with regulating CDKN1C expression and imprinting are separate from those regulating IGF2 imprinting. </p><p>Romanelli et al. (2010) identified 7 novel mutations in the CDKN1C gene in 8 of 50 patients with BWS who did not have epigenetic alterations at chromosome 11q15. Six patients inherited the mutation from apparently asymptomatic mothers, 1 was de novo, and 1 could not be determined. Three of the mutations involved nucleotide 845 (see, e.g., 600856.0004 and 600856.0005), suggesting a possible mutation hotspot. In additional to classic features of the disorder, 2 patients had polydactyly, 2 had an extra nipple, and 3 had cleft palate. No mutations were found in 22 patients with isolated hemihypertrophy, omphalocele, or macroglossia. </p><p><strong><em>IMAGE Syndrome</em></strong></p><p>
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In affected members of a 5-generation Argentinian family with intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies (IMAGE syndrome; 614732) and 4 additional unrelated patients, Arboleda et al. (2012) identified heterozygous mutations in the CDKN1C gene (600856.0007-600856.0011). All 5 IMAGE-associated mutations are clustered in a highly conserved region of CDKN1C, near the PCNA (176740)-binding domain, and result in loss of PCNA binding. Targeted expression of IMAGE-associated CDKN1C mutations in Drosophila caused restricted eye and wing growth, suggesting a gain-of-function mechanism. Familial analysis showed an imprinted mode of inheritance in the Argentinian family, in which only maternal transmission of the mutation resulted in IMAGE syndrome. </p><p><strong><em>Association with Cancer</em></strong></p><p>
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Tokino et al. (1996) examined the CDKN1C gene for genetic alterations in a large number of tumors. Although no somatic mutation was detected, they found several normal variations in this gene, including 4 types of 12-bp in-frame deletions in the proline/alanine repeating domain. </p>
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</span>
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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>Zhang et al. (1997) produced targeted disruption of the p57(KIP2) gene in mice and demonstrated that they have altered cell proliferation and differentiation, leading to abdominal muscle defects; cleft palate; endochondral bone ossification defects with incomplete differentiation of hypertrophic chondrocytes; renal medullary dysplasia; adrenal cortical hyperplasia and cytomegaly; and lens cell hyperproliferation and apoptosis. Since many of these phenotypes are observed in patients with BWS, Zhang et al. (1997) suggested that the observations support a loss of p57(KIP2) expression as having a role in that disorder. Zhang et al. (1997) noted that type X collagen (120110) is expressed in hypertrophic chondrocytes and has been implicated in proper bone development. In mutant mice, expression of type X collagen was significantly reduced in the mutant hypertrophic zone. Thus, the investigators concluded that p57(KIP2) is required for expression of collagen X, and perhaps other genes that facilitate the ossification of chondrocytes. Expression of p57(KIP2) is restricted to the fetal adrenal cortex and presumably plays a role in controlling cell proliferation; its absence leads to adrenal cortex hyperplasia and cytomegaly. </p><p>John et al. (2001) used transgenic mice harboring modified BAC inserts to show that enhancers for expression (within skeletal muscle and cartilage) of the mouse p57Kip2 (Cdkn1c) gene were located at least 25 kb downstream. There was no evidence for allele-specific expression of Cdkn1c from BAC transgenes that spanned 315 kb around the locus. The authors suggested that a key imprinting element for Cdkn1c, as for IGF2, may lie at a distance, and hypothesized that Beckwith-Wiedemann syndrome in humans may result from disruption of appropriate expression of CDKN1C through mutations that occur at a substantial distance from the gene. </p><p>One-third of individuals with Beckwith-Wiedemann syndrome lose maternal-specific methylation at KvDMR1, a putative imprinting control region within intron 10 of the KCNQ1 gene (607542), and it has been proposed that this epimutation results in aberrant imprinting and, consequently, BWS. Fitzpatrick et al. (2002) showed that paternal inheritance of this mutation in mice results in the derepression in cis of 6 genes, including Cdkn1c. Furthermore, fetuses and adult mice that inherited the deletion from their fathers were 20 to 25% smaller than their wildtype littermates. By contrast, maternal inheritance of this deletion had no effect on imprinted gene expression or growth. Thus, the unmethylated paternal KvDMR1 allele regulates imprinted expression by silencing genes on the paternal chromosome. These findings supported the hypothesis that loss of methylation in BWS patients activates the repressive function of KvDMR1 on the maternal chromosome, resulting in abnormal silencing of CDKN1C and the development of BWS. </p>
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</span>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>11 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</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 BECKWITH-WIEDEMANN SYNDROME</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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CDKN1C, GLU47TER
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<br />
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SNP: rs137852766,
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ClinVar: RCV000009287
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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>Hatada et al. (1996) identified a heterozygous glu47-to-ter mutation in a 7-year-old boy with BWS (130650) caused by a C-to-T transition at nucleotide 399. They noted that this mutation would lead to a severely truncated polypeptide of 46 residues with disruption of the Cdk inhibitory domain and loss of the QT domain and the proline/alanine repeats. This mutation disrupts a PstI restriction site; digestion of the PCR-amplified DNA with PstI led to the identification of a novel 219-bp fragment in the patient in addition to 3 other fragments which were also detected in normal individuals. The parents, grandparents, and sister of the patient were healthy. PCR-amplified DNA from the parents was examined, and the mother was found to have the same 219-bp fragment that was present in the mutant allele of the patient. The father of the patient had only the normal allele. Hatada et al. (1996) reported that the mother inherited the abnormal allele from her father. She was phenotypically normal, since p57(KIP2) is expressed from the maternal allele. </p><p>By functional analysis of the glu47-to-ter mutation in the patient reported by Hatada et al. (1996), Bhuiyan et al. (1999) found that the mutation, which occurs in the Cdk inhibitory domain, renders the protein inactive with consequent complete loss of its role as a cell cycle inhibitor and of its nuclear localization. </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 BECKWITH-WIEDEMANN SYNDROME</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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CDKN1C, 1-BP DEL/2-BP INS, 1086T-AG
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<br />
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SNP: rs2133780364,
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ClinVar: RCV000009288
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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>Hatada et al. (1996) described a p57(KIP2) mutation in a 3-month-old girl with BWS (130650). This patient was heterozygous for a T-to-AG mutation at nucleotide 1086 that modified the 9 amino acids downstream, resulting in premature translation termination. The resultant 284-amino acid truncated polypeptide lacks the QT domain. The mutation disrupts an MboII restriction site in the gene. </p><p>By functional analysis of this mutation in the patient reported by Hatada et al. (1996), Bhuiyan et al. (1999) found that the mutant protein, although completely retaining its cell cycle regulatory activity, lacks nuclear localization, and is thus prevented from performing its role as an active cell cycle inhibitor. The mutant allele was inherited from the mother, as was the case with the glu47-to-ter mutation (600856.0001) described by Hatada et al. (1996). </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 BECKWITH-WIEDEMANN SYNDROME</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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CDKN1C, 570CT-G
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<br />
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SNP: rs387906399,
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ClinVar: RCV000009289
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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 familial case of BWS (130650), Hatada et al. (1997) found a heterozygous CT-to-G transversion/deletion at nucleotide 570 of CDKN1C, leading to a frameshift at codon 104 resulting in the loss of the QT domain and the PAPA repeats of the gene product. The patient's father was normal but his mother had gigantism during infancy. The patient's sister also had BWS and showed the same mutation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0004 BECKWITH-WIEDEMANN SYNDROME</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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CDKN1C, SER247TER
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<br />
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SNP: rs104894200,
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ClinVar: RCV000009290
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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 BWS (130650), Hatada et al. (1997) found heterozygosity for a C-to-A transversion at nucleotide 1000 of the CDKN1C gene, changing ser247 (TCG) to a termination (TAG) codon. This resulted in a truncated polypeptide of 246 residues with a disruption of the QT domain. The mutation pointed to an important role of the QT domain in growth regulation. </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 BECKWITH-WIEDEMANN SYNDROME</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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|
CDKN1C, SER282TER, 845C-G
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<br />
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SNP: rs267606716,
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ClinVar: RCV000009291, RCV000521869
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 32-year-old man with BWS (130650), Romanelli et al. (2010) identified a heterozygous 845C-G transversion in the CDKN1C gene, resulting in a ser282-to-ter (S282X) substitution in domain III. He had generalized overgrowth, macroglossia, ear creases, and omphalocele. Other features included cryptorchidism and hypoglycemia. The mutation resulted in the same amino acid change as that found in another patient (845C-A; 600856.0006), suggesting a possible hotspot at this nucleotide. </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>.0006 BECKWITH-WIEDEMANN SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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CDKN1C, SER282TER, 845C-A
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<br />
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|
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SNP: rs267606716,
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|
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ClinVar: RCV000009292
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 7-year-old boy with BWS (130650), Romanelli et al. (2010) identified a heterozygous 845C-A transversion in the CDKN1C gene, resulting in a ser282-to-ter (S282X) substitution in domain III. He had generalized overgrowth, macroglossia, ear creases, and omphalocele. Additional features included cleft palate and an extra nipple. The mutation resulted in the same amino acid change as that found in another patient (845C-G; 600856.0005), suggesting a possible hotspot at this nucleotide. </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 INTRAUTERINE GROWTH RETARDATION, METAPHYSEAL DYSPLASIA, ADRENAL HYPOPLASIA CONGENITA, AND GENITAL ANOMALIES</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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|
CDKN1C, PHE276VAL
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<br />
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|
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SNP: rs387907223,
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|
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ClinVar: RCV004814925
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 7 affected members of a 5-generation Argentinian family with intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies (IMAGE syndrome; 614732), originally reported by Bergada et al. (2005), Arboleda et al. (2012) identified heterozygosity for an 825T-G transversion in the CDKN1C gene, resulting in a phe276-to-val (F276V) substitution at a highly conserved residue near the PCNA (176740)-binding domain. The variant was not present in the dbSNP (build 129) database. Inheritance of IMAGE syndrome was only through maternal transmission of the F276V mutation: sequencing in 24 family members confirmed that only individuals who inherited the 825T-G mutation on the maternal allele were affected, presumably due to epigenetic silencing of the mutated allele when it occurred on the paternal allele. Analysis of transfected HEK293 cells suggested disruption of PCNA binding. Overexpression of the F276V mutant in Drosophila resulted in moderate restriction of wing and eye growth, suggestive of a gain-of-function effect. </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>.0008 INTRAUTERINE GROWTH RETARDATION, METAPHYSEAL DYSPLASIA, ADRENAL HYPOPLASIA CONGENITA, AND GENITAL ANOMALIES</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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CDKN1C, PHE276SER
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<br />
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|
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SNP: rs387907224,
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|
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ClinVar: RCV001596942, RCV004814926
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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 intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies (IMAGE syndrome; 614732), Arboleda et al. (2012) identified heterozygosity for an 826T-C transition in the CDKN1C gene, resulting in a phe276-to-ser (F276S) substitution at a highly conserved residue near the PCNA (176740)-binding domain. The variant was not present in the dbSNP (build 129) database. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0009 INTRAUTERINE GROWTH RETARDATION, METAPHYSEAL DYSPLASIA, ADRENAL HYPOPLASIA CONGENITA, AND GENITAL ANOMALIES</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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CDKN1C, ARG279PRO
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<br />
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SNP: rs318240750,
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ClinVar: RCV004814927
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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 intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies (IMAGE syndrome; 614732), Arboleda et al. (2012) identified heterozygosity for an 835G-C transversion in the CDKN1C gene, resulting in an arg279-to-pro (R279P) substitution at a highly conserved residue near the PCNA (176740)-binding domain. The variant was not present in the dbSNP (build 129) database. </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 INTRAUTERINE GROWTH RETARDATION, METAPHYSEAL DYSPLASIA, ADRENAL HYPOPLASIA CONGENITA, AND GENITAL ANOMALIES</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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CDKN1C, ASP274ASN
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<br />
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SNP: rs387907225,
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ClinVar: RCV001380060, RCV002513231, RCV004814928
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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 intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies (IMAGE syndrome; 614732), Arboleda et al. (2012) identified heterozygosity for an 819G-A transition in the CDKN1C gene, resulting in an asp274-to-asn (D274N) substitution at a highly conserved residue near the PCNA (176740)-binding domain. The variant was not present in the dbSNP (build 129) database. </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 INTRAUTERINE GROWTH RETARDATION, METAPHYSEAL DYSPLASIA, ADRENAL HYPOPLASIA CONGENITA, AND GENITAL ANOMALIES</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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CDKN1C, LYS278GLU
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<br />
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SNP: rs387907226,
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ClinVar: RCV004814929
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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 intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies (IMAGE syndrome; 614732), Arboleda et al. (2012) identified heterozygosity for an 831A-G transition in the CDKN1C gene, resulting in a lys278-to-glu (K278E) substitution at a highly conserved residue near the PCNA (176740)-binding domain. The variant was not present in the dbSNP (build 129) database. Analysis of transfected HEK293 cells suggested disruption of PCNA binding. Overexpression of the K278E mutant in Drosophila resulted in moderate restriction of wing and eye growth, suggestive of a gain-of-function effect. </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>REFERENCES</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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<ol>
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<li>
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<p class="mim-text-font">
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Algar, E., Brickell, S., Deeble, G., Amor, D., Smith, P.
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<strong>Analysis of CDKN1C in Beckwith Wiedemann syndrome.</strong>
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Hum. Mutat. 15: 497-508, 2000.
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[PubMed: 10862080]
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[Full Text: https://doi.org/10.1002/1098-1004(200006)15:6<497::AID-HUMU2>3.0.CO;2-F]
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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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Algar, E. M., Deeble, G. J., Smith, P. J.
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<strong>CDKN1C expression in Beckwith-Wiedemann syndrome patients with allele imbalance.</strong>
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J. Med. Genet. 36: 524-531, 1999.
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[PubMed: 10424812]
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<li>
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<p class="mim-text-font">
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Arboleda, V. A., Lee, H., Parnaik, R., Fleming, A., Banerjee, A., Ferraz-de-Souza, B., Delot, E. C., Rodriguez-Fernandez, I. A., Braslavsky, D., Bergada, I., Dell'Angelica, E. C., Nelson, S. F., Martinez-Agosto, J. A., Achermann, J. C., Vilain, E.
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|
<strong>Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome.</strong>
|
|
Nature Genet. 44: 788-792, 2012.
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[PubMed: 22634751]
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[Full Text: https://doi.org/10.1038/ng.2275]
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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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Bergada, I., del Rey, G., Lapunzina, P., Bergada, C., Fellous, M., Copelli, S.
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<strong>Familial occurrence of the IMAGe association: additional clinical variants and a proposed mode of inheritance.</strong>
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J. Clin. Endocr. Metab. 90: 3186-3190, 2005.
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[PubMed: 15769992]
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[Full Text: https://doi.org/10.1210/jc.2004-1589]
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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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Bhuiyan, Z. A., Yatsuki, H., Sasaguri, T., Joh, K., Soejima, H., Zhu, X., Hatada, I. Morisaki, H., Morisaki, T., Mukai, T.
|
|
<strong>Functional analysis of the p57(KIP2) gene mutation in Beckwith-Wiedemann syndrome.</strong>
|
|
Hum. Genet. 104: 205-210, 1999.
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[PubMed: 10323243]
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[Full Text: https://doi.org/10.1007/s004390050937]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Diaz-Meyer, N., Yang, Y., Sait, S. N., Maher, E. R., Higgins, M. J.
|
|
<strong>Alternative mechanisms associated with silencing of CDKN1C in Beckwith-Wiedemann syndrome.</strong>
|
|
J. Med. Genet. 42: 648-655, 2005.
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[PubMed: 16061564]
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[Full Text: https://doi.org/10.1136/jmg.2004.030593]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Du, M., Beatty, L. G., Zhou, W., Lew, J., Schoenherr, C., Weksberg, R., Sadowski, P. D.
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|
<strong>Insulator and silencer sequences in the imprinted region of human chromosome 11p15.5.</strong>
|
|
Hum. Molec. Genet. 12: 1927-1939, 2003.
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[PubMed: 12874112]
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[Full Text: https://doi.org/10.1093/hmg/ddg194]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Fisher, R. A., Hodges, M. D., Rees, H. C., Sebire, N. J., Seckl, M. J., Newlands, E. S., Genest, D. R., Castrillon, D. H.
|
|
<strong>The maternally transcribed gene p57(KIP2) (CDNK1C) is abnormally expressed in both androgenetic and biparental complete hydatidiform moles.</strong>
|
|
Hum. Molec. Genet. 11: 3267-3272, 2002.
|
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|
|
[PubMed: 12471053]
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[Full Text: https://doi.org/10.1093/hmg/11.26.3267]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Fitzpatrick, G. V., Soloway, P. D., Higgins, M. J.
|
|
<strong>Regional loss of imprinting and growth deficiency in mice with a targeted deletion of KvDMR1.</strong>
|
|
Nature Genet. 32: 426-431, 2002.
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[PubMed: 12410230]
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[Full Text: https://doi.org/10.1038/ng988]
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</p>
|
|
</li>
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<li>
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<p class="mim-text-font">
|
|
Hang, C. T., Yang, J., Han, P., Cheng, H.-L., Shang, C., Ashley, E., Zhou, B., Chang, C.-P.
|
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<strong>Chromatin regulation by Brg1 underlies heart muscle development and disease.</strong>
|
|
Nature 466: 62-67, 2010. Note: Erratum: Nature 475: 532 only, 2011.
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|
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|
|
[PubMed: 20596014]
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|
[Full Text: https://doi.org/10.1038/nature09130]
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|
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</p>
|
|
</li>
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|
<li>
|
|
<p class="mim-text-font">
|
|
Hatada, I., Mukai, T.
|
|
<strong>Genomic imprinting of p57(KIP2), a cyclin-dependent kinase inhibitor, in mouse.</strong>
|
|
Nature Genet. 11: 204-206, 1995.
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|
|
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|
|
[PubMed: 7550351]
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|
|
[Full Text: https://doi.org/10.1038/ng1095-204]
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|
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Hatada, I., Nabetani, A., Morisaki, H., Xin, Z., Ohishi, S., Tonoki, H., Niikawa, N., Inoue, M., Komoto, Y., Okada, A., Steichen, E., Ohashi, H., Fukushima, Y., Nakayama, M., Mukai, T.
|
|
<strong>New p57(KIP2) mutations in Beckwith-Wiedemann syndrome.</strong>
|
|
Hum. Genet. 100: 681-683, 1997.
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|
|
[PubMed: 9341892]
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|
[Full Text: https://doi.org/10.1007/s004390050573]
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|
|
</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Hatada, I., Ohashi, H., Fukushima, Y., Kaneko, Y., Inoue, M., Komoto, Y., Okada, A., Ohishi, S., Nabetani, A., Morisaki, H., Nakayama, M., Niikawa, M,, Mukai, T.
|
|
<strong>An imprinted gene p57(KIP2) is mutated in Beckwith-Wiedemann syndrome.</strong>
|
|
Nature Genet. 14: 171-173, 1996.
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|
|
|
|
[PubMed: 8841187]
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|
|
[Full Text: https://doi.org/10.1038/ng1096-171]
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|
|
|
|
</p>
|
|
</li>
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<li>
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<p class="mim-text-font">
|
|
John, R. M., Ainscough, J. F.-X., Barton, S. C., Surani, M. A.
|
|
<strong>Distant cis-elements regulate imprinted expression of the mouse p57(Kip2) (Cdkn1c) gene: implications for the human disorder, Beckwith-Wiedemann syndrome.</strong>
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|
Hum. Molec. Genet. 10: 1601-1609, 2001.
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[PubMed: 11468278]
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[Full Text: https://doi.org/10.1093/hmg/10.15.1601]
|
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|
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|
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Lam, W. W. K., Hatada, I., Ohishi, S., Mukai, T., Joyce, J. A., Cole, T. R. P., Donnai, D., Reik, W., Schofield, P. N., Maher, E. R.
|
|
<strong>Analysis of germline CDKN1C (p57-KIP2) mutations in familial and sporadic Beckwith-Wiedemann syndrome (BWS) provides a novel genotype-phenotype correlation.</strong>
|
|
J. Med. Genet. 36: 518-523, 1999.
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[PubMed: 10424811]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Lee, M. P., DeBaun, M., Randhawa, G., Reichard, B. A., Elledge, S. J., Feinberg, A. P.
|
|
<strong>Low frequency of p57(KIP2) mutation in Beckwith-Wiedemann syndrome.</strong>
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|
Am. J. Hum. Genet. 61: 304-309, 1997.
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[PubMed: 9311734]
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[Full Text: https://doi.org/10.1086/514858]
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|
|
</p>
|
|
</li>
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<li>
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|
<p class="mim-text-font">
|
|
Lee, M.-H., Reynisdottir, I., Massague, J.
|
|
<strong>Cloning of p57(KIP2), a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution.</strong>
|
|
Genes Dev. 9: 639-649, 1995.
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|
|
|
|
[PubMed: 7729683]
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|
|
[Full Text: https://doi.org/10.1101/gad.9.6.639]
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|
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</p>
|
|
</li>
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|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Matsuoka, S., Edwards, M. C., Bai, C., Parker, S., Zhang, P., Baldini, A., Harper, J. W., Elledge, S. J.
|
|
<strong>p57(KIP2), a structurally distinct member of the p21(CIP1) Cdk inhibitor family, is a candidate tumor suppressor gene.</strong>
|
|
Genes Dev. 9: 650-662, 1995.
|
|
|
|
|
|
[PubMed: 7729684]
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|
[Full Text: https://doi.org/10.1101/gad.9.6.650]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Matsuoka, S., Thompson, J. S., Edwards, M. C., Barletta, J. M., Grundy, P., Kalikin, L. M., Harper, J. W., Elledge, S. J., Feinberg, A. P.
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|
<strong>Imprinting of the gene encoding a human cyclin-dependent kinase inhibitor, p57(KIP2), on chromosome 11p15.</strong>
|
|
Proc. Nat. Acad. Sci. 93: 3026-3030, 1996.
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|
|
[PubMed: 8610162]
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[Full Text: https://doi.org/10.1073/pnas.93.7.3026]
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</p>
|
|
</li>
|
|
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<li>
|
|
<p class="mim-text-font">
|
|
O'Keefe, D., Dao, D., Zhao, L., Sanderson, R., Warburton, D., Weiss, L., Anyane-Yeboa, K., Tycko, B.
|
|
<strong>Coding mutations in p57(KIP2) are present in some cases of Beckwith-Wiedemann syndrome but are rare or absent in Wilms tumors.</strong>
|
|
Am. J. Hum. Genet. 61: 295-303, 1997.
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|
|
|
|
|
[PubMed: 9311733]
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|
|
[Full Text: https://doi.org/10.1086/514854]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Romanelli, V., Belinchon, A., Benito-Sanz, S., Martinez-Glez, V., Gracia-Bouthelier, R., Heath, K. E., Campos-Barros, A., Garcia-Minaur, S., Fernandez, L., Meneses, H., Lopez-Siguero, J. P., Guillen-Navarro, E., and 9 others.
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|
<strong>CDKN1C (p57(Kip2)) analysis in Beckwith-Wiedemann syndrome (BWS) patients: Genotype-phenotype correlations, novel mutations, and polymorphisms.</strong>
|
|
Am. J. Med. Genet. 152A: 1390-1397, 2010.
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|
[PubMed: 20503313]
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[Full Text: https://doi.org/10.1002/ajmg.a.33453]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Scandura, J. M., Boccuni, P., Massague, J., Nimer, S. D.
|
|
<strong>Transforming growth factor beta-induced cell cycle arrest of human hematopoietic cells requires p57KIP2 upregulation.</strong>
|
|
Proc. Nat. Acad. Sci. 101: 15231-15236, 2004. Note: Erratum: Proc. Nat. Acad. Sci. 101: 16707 only, 2004.
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[PubMed: 15477587]
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[Full Text: https://doi.org/10.1073/pnas.0406771101]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Sood, R., Zehnder, J. L., Druzin, M. L., Brown, P. O.
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<strong>Gene expression patterns in human placenta.</strong>
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Proc. Nat. Acad. Sci. 103: 5478-5483, 2006.
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[PubMed: 16567644]
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[Full Text: https://doi.org/10.1073/pnas.0508035103]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Tokino, T., Urano, T., Furuhata, T., Matsushima, M., Miyatsu, T., Sasaki, S., Nakamura, Y.
|
|
<strong>Characterization of the human p57(KIP2) gene: alternative splicing, insertion/deletion polymorphisms in VNTR sequences in the coding region, and mutational analysis.</strong>
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|
Hum. Genet. 97: 625-631, 1996.
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|
[PubMed: 8655143]
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[Full Text: https://doi.org/10.1007/BF02281873]
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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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Zhang, P., Leigeois, N. J., Wong, C., Finegold, M., Hou, H., Thompson, J. C., Silverman, A., Harper, J. W., DePinho, R. A., Elledge, S. J.
|
|
<strong>Altered cell differentiation and proliferation in mice lacking p57(KIP2) indicates a role in Beckwith-Wiedemann syndrome.</strong>
|
|
Nature 387: 151-158, 1997.
|
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|
|
[PubMed: 9144284]
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[Full Text: https://doi.org/10.1038/387151a0]
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</p>
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</li>
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</ol>
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<div>
|
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<br />
|
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</div>
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</div>
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</div>
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<div>
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<div class="row">
|
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
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<span class="text-nowrap mim-text-font">
|
|
Contributors:
|
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</span>
|
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 7/20/2012<br>Cassandra L. Kniffin - updated : 11/29/2010<br>Ada Hamosh - updated : 9/27/2010<br>Anne M. Stumpf - updated : 8/4/2006<br>Ada Hamosh - updated : 8/4/2006<br>Marla J. F. O'Neill - updated : 9/13/2005<br>George E. Tiller - updated : 5/9/2005<br>Patricia A. Hartz - updated : 11/16/2004<br>George E. Tiller - updated : 9/13/2004<br>Victor A. McKusick - updated : 9/13/2002<br>George E. Tiller - updated : 12/18/2001<br>Victor A. McKusick - updated : 6/30/2000<br>Michael J. Wright - updated : 8/16/1999<br>Victor A. McKusick - updated : 4/23/1999<br>Victor A. McKusick - updated : 10/7/1997<br>Victor A. McKusick - updated : 9/24/1997<br>Victor A. McKusick - updated : 5/9/1997<br>Moyra Smith - updated : 10/2/1996
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Victor A. McKusick : 10/11/1995
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