3348 lines
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- *103280 - H19, IMPRINTED MATERNALLY EXPRESSED NONCODING TRANSCRIPT; H19
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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">*103280</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="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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="#molecularGenetics">Molecular Genetics</a>
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<a href="#evolution">Evolution</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000130600;t=ENST00000414790" 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=283120" 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=103280" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000130600;t=ENST00000414790" 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</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NR_002196,NR_131223,NR_131224,NR_185828,NR_185829,NR_185830,NR_185831" 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://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=103280" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.proteinatlas.org/search/H19" 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>
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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=283120" 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=ENSG00000130600;t=ENST00000414790" 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=H19" 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=H19" 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+283120" 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/H19" 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:283120" 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/283120" 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=ENST00000710492.1&hgg_start=1995176&hgg_end=2001266&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:4713" 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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=103280[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 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 id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=103280[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://gnomad.broadinstitute.org/gene/ENSG00000130600" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=H19" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=H19" 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="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=H19&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/PA29091" 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 style="display: table-cell;">Animal Models</div>
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<div><a href="https://www.alliancegenome.org/gene/HGNC:4713" 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="http://v1.marrvel.org/search/gene/H19#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="https://www.ncbi.nlm.nih.gov/gene/283120/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=283120" 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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<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 class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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103280
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H19, IMPRINTED MATERNALLY EXPRESSED NONCODING TRANSCRIPT; H19
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<span class="mim-font">
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LONG INTERGENIC NONCODING RNA H19<br />
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lincRNA H19<br />
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ADULT SKELETAL MUSCLE GENE; ASM<br />
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ASM1
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</h4>
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=H19" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">H19</a></em></strong>
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<strong>
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Cytogenetic location: <a href="/geneMap/11/69?start=-3&limit=10&highlight=69">11p15.5</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr11:1995176-2001266&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'})">11:1,995,176-2,001,266</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>Description</strong>
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<p>The H19 gene encodes a sequence that is not translated and that is expressed exclusively from the maternal allele. The H19/IGF2-imprinting control region (ICR1; <a href="/entry/616186">616186</a>), which is located just upstream of H19, coordinates expression of H19 and IGF2 (<a href="/entry/147470">147470</a>), which is expressed exclusively from the paternal allele (summary by <a href="#3" class="mim-tip-reference" title="Bartholdi, D., Krajewska-Walasek, M., Ounap, K., Gaspar, H., Chrzanowska, K. H., Ilyana, H., Kayserili, H., Lurie, I. W., Schinzel, A., Baumer, A. <strong>Epigenetic mutations of the imprinted IGF2-H19 domain in Silver-Russell syndrome (SRS): results from a large cohort of patients with SRS and SRS-like phenotypes. (Letter)</strong> J. Med. Genet. 46: 192-197, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19066168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19066168</a>] [<a href="https://doi.org/10.1136/jmg.2008.061820" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19066168">Bartholdi et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19066168" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The noncoding H19 RNA functions as the primary transcript for microRNA-675 (MIR675; <a href="/entry/615509">615509</a>) (<a href="#9" class="mim-tip-reference" title="Cai, X., Cullen, B. R. <strong>The imprinted H19 noncoding RNA is a primary microRNA precursor.</strong> RNA 13: 313-316, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17237358/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17237358</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17237358[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/10.1261/rna.351707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17237358">Cai and Cullen, 2007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17237358" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="cloning" class="mim-anchor"></a>
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>Cloning and Expression</strong>
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<p><a href="#22" class="mim-tip-reference" title="Leibovitch, M. P., Nguyen, V. C., Gross, M. S., Solhonne, B., Leibovitch, S. A., Bernheim, A. <strong>The human ASM (adult skeletal muscle) gene: expression and chromosomal assignment to 11p15.</strong> Biochem. Biophys. Res. Commun. 180: 1241-1250, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1953776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1953776</a>] [<a href="https://doi.org/10.1016/s0006-291x(05)81329-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1953776">Leibovitch et al. (1991)</a> used a rat skeletal muscle probe originating from a rhabdomyosarcoma to isolate a cDNA probe from a human placental cDNA library. In the rat, while the corresponding mRNA and protein were not expressed in fetal muscle, an increasing accumulation of the corresponding mRNA and protein were observed during postnatal development of skeletal muscle, and this accumulation was maximal in adulthood. As no expression was found in any other tissue, the gene was referred to as the adult skeletal muscle (ASM) gene. A gene coding for an abundant fetal transcript in mice had been identified by <a href="#26" class="mim-tip-reference" title="Pachnis, V., Belayew, A., Tilghman, S. M. <strong>Locus unlinked to alpha-fetoprotein under the control of the murine raf and Rif genes.</strong> Proc. Nat. Acad. Sci. 81: 5523-5527, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6206499/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6206499</a>] [<a href="https://doi.org/10.1073/pnas.81.17.5523" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6206499">Pachnis et al. (1984)</a>, who designated it H19. The H19 gene is expressed in a number of organs during a restricted period of fetal development, and in embryonal carcinoma cells after induction of differentiation (<a href="#4" class="mim-tip-reference" title="Bartolomei, M. S., Zemel, S., Tilghman, S. M. <strong>Parental imprinting of the mouse H19 gene.</strong> Nature 351: 153-155, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1709450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1709450</a>] [<a href="https://doi.org/10.1038/351153a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1709450">Bartolomei et al., 1991</a>). The gene shows a restricted pattern of expression in adult tissues; expression is confined to skeletal and cardiac muscle. <a href="#22" class="mim-tip-reference" title="Leibovitch, M. P., Nguyen, V. C., Gross, M. S., Solhonne, B., Leibovitch, S. A., Bernheim, A. <strong>The human ASM (adult skeletal muscle) gene: expression and chromosomal assignment to 11p15.</strong> Biochem. Biophys. Res. Commun. 180: 1241-1250, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1953776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1953776</a>] [<a href="https://doi.org/10.1016/s0006-291x(05)81329-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1953776">Leibovitch et al. (1991)</a> presented evidence that the human H19 gene has a transcript that gives rise to a 29-kD protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1953776+6206499+1709450" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Cai, X., Cullen, B. R. <strong>The imprinted H19 noncoding RNA is a primary microRNA precursor.</strong> RNA 13: 313-316, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17237358/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17237358</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17237358[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/10.1261/rna.351707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17237358">Cai and Cullen (2007)</a> determined that the 23-nucleotide MIR675 originates from nucleotides 1014 to 1036 of the noncoding human H19 transcript. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17237358" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Gene Function</strong>
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<p><strong><em>Function of H19</em></strong></p><p>
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H19 is a developmentally regulated gene with putative tumor suppressor activity; it had been hypothesized that loss of H19 expression may be involved in Wilms tumorigenesis. <a href="#16" class="mim-tip-reference" title="Han, D. K. M., Khaing, Z. Z., Pollock, R. A., Haudenschild, C. C., Liau, G. <strong>H19, a marker of developmental transition, is reexpressed in human atherosclerotic plaques and is regulated by the insulin family of growth factors in cultured rabbit smooth muscle cells.</strong> J. Clin. Invest. 97: 1276-1285, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8636440/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8636440</a>] [<a href="https://doi.org/10.1172/JCI118543" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8636440">Han et al. (1996)</a> performed in situ hybridization analysis of H19 expression during normal rabbit development and in human atherosclerotic plaques. They found that H19 expression in developing skeletal and smooth muscles correlated with specific differentiation events in these tissues. Expression of H19 in skeletal muscle correlated with nonproliferative, actin-positive muscle cells. In the prenatal blood vessel, H19 expression was both temporally and spatially regulated with initial loss of expression in the inner smooth muscle layers adjacent to the lumen. <a href="#16" class="mim-tip-reference" title="Han, D. K. M., Khaing, Z. Z., Pollock, R. A., Haudenschild, C. C., Liau, G. <strong>H19, a marker of developmental transition, is reexpressed in human atherosclerotic plaques and is regulated by the insulin family of growth factors in cultured rabbit smooth muscle cells.</strong> J. Clin. Invest. 97: 1276-1285, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8636440/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8636440</a>] [<a href="https://doi.org/10.1172/JCI118543" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8636440">Han et al. (1996)</a> also identified H19-positive cells in adult atherosclerotic lesions, suggesting that these cells may recapitulate early developmental events. These results, along with the identification of the insulin family of growth factors as potent regulatory molecules for H19 expression, provided additional clues toward understanding the physiologic regulation and function of H19. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8636440" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Genes expressed during embryogenesis, downregulated with tissue maturation and reexpressed in cancer, are designated oncofetal genes, and many of them are used as tumor markers. <a href="#1" class="mim-tip-reference" title="Ariel, I., Ayesh, S., Perlman, E. J., Pizov, G., Tanos, V., Schneider, T., Erdmann, V. A., Podeh, D., Komitowski, D., Quasem, A. S., de Groot, N., Hochberg, A. <strong>The product of the imprinted H19 gene is an oncofetal RNA.</strong> Molec. Path. 50: 34-44, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9208812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9208812</a>] [<a href="https://doi.org/10.1136/mp.50.1.34" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9208812">Ariel et al. (1997)</a> showed oncofetal expression of H19 in human cancer. The study of H19 expression in testicular germ cell tumors of adolescents and young adults, which follow lines of differentiation of the conceptus, demonstrated dissociation between level of expression and monoallelic versus biallelic expression, which are 2 independent oncofetal characteristics of cancer. <a href="#2" class="mim-tip-reference" title="Ariel, I., de Groot, N., Hochberg, A. <strong>Imprinted H19 gene expression in embryogenesis and human cancer: the oncofetal connection.</strong> Am. J. Med. Genet. 91: 46-50, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10751088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10751088</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(20000306)91:1<46::aid-ajmg8>3.0.co;2-i" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10751088">Ariel et al. (2000)</a> reported that H19 is abundantly expressed in the fetal bladder mucosa and in carcinoma of the urinary bladder. It could be used as a marker of early recurrence and potentially as the basis for gene therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9208812+10751088" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 real-time PCR, <a href="#12" class="mim-tip-reference" title="Dudek, K. A., Lafont, J. E., Martinez-Sanchez, A., Murphy, C. L. <strong>Type II collagen expression is regulated by tissue-specific miR-675 in human articular chondrocytes.</strong> J. Biol. Chem. 285: 24381-24387, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20529846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20529846</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20529846[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/10.1074/jbc.M110.111328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20529846">Dudek et al. (2010)</a> found comparably high expression of Mir675, H19, and the master chondrocyte regulator Sox9 (<a href="/entry/608160">608160</a>) in adult mouse cartilage. Expression of H19, MIR675, SOX9, and collagen-2A1 (COL2A1; <a href="/entry/120140">120140</a>) decreased with increasing passage number in chondrocytes cultured from juvenile and adult human articular cartilage. Depletion of SOX9 or H19 in human chondrocytes significantly reduced COL2A1 mRNA content and COL2A1 protein secretion. Overexpression of MIR675 reversed the effects of SOX9 or H19 depletion. <a href="#12" class="mim-tip-reference" title="Dudek, K. A., Lafont, J. E., Martinez-Sanchez, A., Murphy, C. L. <strong>Type II collagen expression is regulated by tissue-specific miR-675 in human articular chondrocytes.</strong> J. Biol. Chem. 285: 24381-24387, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20529846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20529846</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20529846[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/10.1074/jbc.M110.111328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20529846">Dudek et al. (2010)</a> concluded that SOX9 functions through H19-derived MIR675 to increase COL2A1 expression in chondrocytes, possibly by inhibiting expression of a COL2A1 repressor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20529846" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>NOMO1 (<a href="/entry/609157">609157</a>) antagonizes NODAL signaling (<a href="/entry/601265">601265</a>), which is critical for regulation of trophoblast cell growth. <a href="#14" class="mim-tip-reference" title="Gao, W., Liu, M., Yang, Y., Yang, H., Liao, Q., Bai, Y., Li, Y., Li, D., Peng, C., Wang, Y.-L. <strong>The imprinted H19 gene regulates human placental trophoblast cell proliferation via encoding miR-675 that targets Nodal Modulator 1 (NOMO1).</strong> RNA Biol. 9: 1002-1010, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22832245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22832245</a>] [<a href="https://doi.org/10.4161/rna.20807" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22832245">Gao et al. (2012)</a> found that H19-derived MIR675 suppressed cell proliferation and promoted NODAL-mediated SMAD2 (<a href="/entry/601366">601366</a>) phosphorylation in human trophoblastic JEG-3 cells by directly inhibiting NOMO1 mRNA translation. Overexpression of NOMO1 reversed these effects. Knockdown of H19 or inhibition of MIR675 increased NOMO1 protein expression and promoted JEG-3 cell proliferation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22832245" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Imprinting of H19</em></strong></p><p>
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<a href="#34" class="mim-tip-reference" title="Zhang, Y., Tycko, B. <strong>Monoallelic expression of the human H19 gene.</strong> Nature Genet. 1: 40-44, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1363808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1363808</a>] [<a href="https://doi.org/10.1038/ng0492-40" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1363808">Zhang and Tycko (1992)</a> found restriction site polymorphisms in the human H19 gene and, by examination of the representation of these polymorphisms in cDNAs from fetal organs, demonstrated that H19 expression was largely or exclusively from a single allele. Expression of the WT1 gene (<a href="/entry/607102">607102</a>), which, like H19, maps to 11p and shows fetal expression, was found to have biallelic expression. In the context of previous studies of allelic losses in 11p15 in human embryonal tumors, the findings of <a href="#34" class="mim-tip-reference" title="Zhang, Y., Tycko, B. <strong>Monoallelic expression of the human H19 gene.</strong> Nature Genet. 1: 40-44, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1363808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1363808</a>] [<a href="https://doi.org/10.1038/ng0492-40" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1363808">Zhang and Tycko (1992)</a> supported the possibility of single-step inactivation of monoallelically expressed growth-regulating genes in human oncogenesis. It was not determined in this study whether the expression was uniparental to indicate parental imprinting. The H19 gene and 2 other genes, IGF2 (<a href="/entry/147470">147470</a>) and IGF2 receptor (IGF2R; <a href="/entry/147280">147280</a>), show monoallelic expression in mice. IGF2 is, like H19, located in 11p15. <a href="#34" class="mim-tip-reference" title="Zhang, Y., Tycko, B. <strong>Monoallelic expression of the human H19 gene.</strong> Nature Genet. 1: 40-44, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1363808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1363808</a>] [<a href="https://doi.org/10.1038/ng0492-40" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1363808">Zhang and Tycko (1992)</a> commented that, if IGF2 also shows monoallelic expression, it may indicate that that region is a 'hotspot' for this phenomenon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1363808" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>From the study of the androgenetic complete hydatidiform mole, <a href="#28" class="mim-tip-reference" title="Rachmilewitz, J., Goshen, R., Ariel, I., Schneider, T., de Groot, N., Hochberg, A. <strong>Parental imprinting of the human H19 gene.</strong> FEBS Lett. 309: 25-28, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1380925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1380925</a>] [<a href="https://doi.org/10.1016/0014-5793(92)80731-u" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1380925">Rachmilewitz et al. (1992)</a> presented strong evidence of parental imprinting of the human H19 gene, with the maternally derived allele as the active one. Furthermore, they showed that the paternally derived allele of the IGF2 is expressed. Thus, the situation in the human is the same as that in the mouse. <a href="#29" class="mim-tip-reference" title="Rainier, S., Johnson, L. A., Dobry, C. J., Ping, A. J., Grundy, P. E., Feinberg, A. P. <strong>Relaxation of imprinted genes in human cancer.</strong> Nature 362: 747-749, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8385745/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8385745</a>] [<a href="https://doi.org/10.1038/362747a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8385745">Rainier et al. (1993)</a> found that both H19 and IGF2 show monoallelic expression in human tissues and that, as in mouse, H19 is expressed from the maternal allele and IGF2 from the paternal allele. In contrast, 69% of Wilms tumors not undergoing loss of heterozygosity at 11p showed biallelic expression of one or both genes, suggesting that relaxation or loss of imprinting may represent a new epigenetic mutational mechanism in carcinogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1380925+8385745" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Mutter, G. L., Stewart, C. L., Chaponot, M. L., Pomponio, R. J. <strong>Oppositely imprinted genes H19 and insulin-like growth factor 2 are coexpressed in human androgenetic trophoblast.</strong> Am. J. Hum. Genet. 53: 1096-1102, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7692725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7692725</a>]" pmid="7692725">Mutter et al. (1993)</a> found that normal gestations express H19 only from the maternal allele and express IGF2 from the paternal allele, whereas neither is expressed from the maternal genome of gynogenetic gestations, and both are expressed from the paternal genome of androgenetic gestations. Coexpression of H19 and IGF2 in the androgenetic tissues was in a single population of cells, mononuclear trophoblast--the same cell type expressing these genes in biparental placentas. These results demonstrated that a biparental genome may be required for expression of the reciprocal IGF2/H19 imprint. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7692725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 the mouse, the imprinted H19 gene, which encodes an untranslated RNA, lies at the end of a cluster of imprinted genes. <a href="#23" class="mim-tip-reference" title="Leighton, P. A., Ingram, R. S., Eggenschwiler, J., Efstratiadis, A., Tilghman, S. M. <strong>Disruption of imprinting caused by deletion of the H19 gene region in mice.</strong> Nature 375: 34-39, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7536897/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7536897</a>] [<a href="https://doi.org/10.1038/375034a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7536897">Leighton et al. (1995)</a> found that imprinting of the insulin-2 gene and the insulin-like growth factor-2 gene, which lie about 100 kb upstream of H19, can be disrupted by maternal inheritance of a targeted deletion of the H19 gene and its flanking sequence. Animals inheriting the H19 mutation from their mothers were 27% heavier than those inheriting from their fathers. Paternal inheritance of the disruption had no effect, which presumably reflects the normally silent state of the paternal gene. The somatic overgrowth of heterozygotes for the maternal deletion was attributed to a gain-of-function of the Igf2 gene rather than a loss of function of H19. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7536897" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>H19 is abundantly expressed in both extraembryonic and fetal tissues. <a href="#19" class="mim-tip-reference" title="Jinno, Y., Ikeda, Y., Yun, K., Maw, M., Masuzaki, H., Fukuda, H., Inuzuka, K., Fujishita, A., Ohtani, Y., Okimoto, T., Ishimaru, T., Niikawa, N. <strong>Establishment of functional imprinting of the H19 gene in human developing placentae.</strong> Nature Genet. 10: 318-324, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7670470/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7670470</a>] [<a href="https://doi.org/10.1038/ng0795-318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7670470">Jinno et al. (1995)</a> found that H19 is monoallelically (maternally) expressed in the human placenta after 10 weeks of gestation, whereas it is biallelically expressed at earlier stages. Regardless of H19 biallelic or monoallelic expression, IGF2 is monoallelically (paternally) expressed in the placenta. Furthermore, with in situ mRNA hybridization using placenta showing H19 biallelic and IGF2 monoallelic expression, they demonstrated that defined cell types simultaneously contained both H19 and IGF2 transcripts. Therefore, the reciprocal linkage of H19 and IGF2 expression demonstrated in Wilms tumors is not observed in placentas. Furthermore, <a href="#19" class="mim-tip-reference" title="Jinno, Y., Ikeda, Y., Yun, K., Maw, M., Masuzaki, H., Fukuda, H., Inuzuka, K., Fujishita, A., Ohtani, Y., Okimoto, T., Ishimaru, T., Niikawa, N. <strong>Establishment of functional imprinting of the H19 gene in human developing placentae.</strong> Nature Genet. 10: 318-324, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7670470/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7670470</a>] [<a href="https://doi.org/10.1038/ng0795-318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7670470">Jinno et al. (1995)</a> found that, unlike methylation analyses of the human H19 gene, the promoter region of the human H19 gene is hypomethylated at all stages of placental development. In contrast, allele-dependent methylation of the 3-prime portion of the gene increases with gestational age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7670470" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Pfeifer, K., Leighton, P. A., Tilghman, S. M. <strong>The structural H19 gene is required for transgene imprinting.</strong> Proc. Nat. Acad. Sci. 93: 13876-13883, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8943029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8943029</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=8943029[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.93.24.13876" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8943029">Pfeifer et al. (1996)</a> stated that the H19 gene and its 5-prime-flanking sequence are required for the genomic imprinting of 2 paternally expressed genes in mice, Ins2 and Igf2, that lie 90 and 115 kb 5-prime to the H19 gene, respectively. <a href="#27" class="mim-tip-reference" title="Pfeifer, K., Leighton, P. A., Tilghman, S. M. <strong>The structural H19 gene is required for transgene imprinting.</strong> Proc. Nat. Acad. Sci. 93: 13876-13883, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8943029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8943029</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=8943029[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.93.24.13876" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8943029">Pfeifer et al. (1996)</a> investigated the role of the H19 gene in its own imprinting by introducing a Mus spretus H19 gene into heterologous locations in the mouse genome. They found that multiple copies of the transgene were sufficient for its paternal silencing and DNA methylation. Replacing the H19 structural gene with a luciferase reporter gene resulted in loss of imprinting of the transgene; that is, high expression and low levels of DNA methylation were observed with both paternal and maternal inheritance. Removal of 701 bp at the 5-prime end of the structural H19 gene resulted in a similar loss of paternal-specific DNA methylation, arguing that those sequences are required for both the establishment and maintenance of the sperm-specific gametic mark. The M. spretus H19 transgene could not rescue the loss of IGF2 imprinting in trans in H19 deletion mice, implying a cis requirement for the H19 gene. In contrast to a previous report (<a href="#8" class="mim-tip-reference" title="Brunkow, M. E., Tilghman, S. M. <strong>Ectopic expression of the H19 gene in mice causes prenatal lethality.</strong> Genes Dev. 5: 1092-1101, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2044956/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2044956</a>] [<a href="https://doi.org/10.1101/gad.5.6.1092" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2044956">Brunkow and Tilghman, 1991</a>) in which overexpression of a marked H19 gene was a prenatal lethal, <a href="#27" class="mim-tip-reference" title="Pfeifer, K., Leighton, P. A., Tilghman, S. M. <strong>The structural H19 gene is required for transgene imprinting.</strong> Proc. Nat. Acad. Sci. 93: 13876-13883, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8943029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8943029</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=8943029[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.93.24.13876" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8943029">Pfeifer et al. (1996)</a> found that expression of the M. spretus transgene had no deleterious effect, leading them to conclude that the 20-bp insertion in the marked gene created a neomorphic mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2044956+8943029" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Davis, T. L., Yang, G. J., McCarrey, J. R., Bartolomei, M. S. <strong>The H19 methylation imprint is erased and re-established differentially on the parental alleles during male germ cell development.</strong> Hum. Molec. Genet. 9: 2885-2894, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11092765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11092765</a>] [<a href="https://doi.org/10.1093/hmg/9.19.2885" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11092765">Davis et al. (2000)</a> analyzed the allelic methylation patterns of the maternally expressed, paternally methylated H19 gene during gametogenesis in the mouse embryo. Both parental alleles were devoid of methylation in male and female midgestation embryonic germ cells, suggesting that methylation imprints are erased in the germ cells prior to this time. In addition, the subsequent hypermethylation of the paternal and maternal alleles in the male germline occurred at different times. Although the paternal allele became hypermethylated during fetal stages, methylation of the maternal allele began during perinatal stages and continued postnatally through the onset of meiosis. The differential acquisition of methylation on the parental H19 alleles during gametogenesis may imply that the 2 unmethylated alleles can still be distinguished from each other. The authors concluded that in the absence of DNA methylation, other epigenetic mechanisms may maintain parental identity at the H19 locus during male germ cell development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11092765" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The expression of the IGF2 (<a href="/entry/147470">147470</a>) and H19 genes is imprinted. Although these neighboring genes share an enhancer, H19 is expressed only from the maternal allele, and IGF2 only from the paternally inherited allele. The region of paternal-specific methylation upstream of H19 appears to be the site of an epigenetic mark that is required for the imprinting of these genes. A deletion within this region results in loss of imprinting of both H19 and IGF2 (<a href="#31" class="mim-tip-reference" title="Thorvaldsen, J. L., Duran, K. L., Bartolomei, M. S. <strong>Deletion of the H19 differentially methylated domain results in loss of imprinted expression of H19 and Igf2.</strong> Genes Dev. 12: 3693-3702, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9851976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9851976</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9851976[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gad.12.23.3693" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9851976">Thorvaldsen et al., 1998</a>). <a href="#5" class="mim-tip-reference" title="Bell, A. C., Felsenfeld, G. <strong>Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene.</strong> Nature 405: 482-485, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839546</a>] [<a href="https://doi.org/10.1038/35013100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839546">Bell and Felsenfeld (2000)</a> showed that this methylated region contains an element that blocks enhancer activity. The activity of this element is dependent upon the vertebrate enhancer-blocking protein CTCF (<a href="/entry/604167">604167</a>). Methylation of CpGs within the CTCF binding sites eliminates binding of CTCF in vitro, and deletion of these sites results in loss of enhancer-blocking activity in vivo, thereby allowing gene expression. This CTCF-dependent enhancer-blocking element acts as an insulator. <a href="#5" class="mim-tip-reference" title="Bell, A. C., Felsenfeld, G. <strong>Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene.</strong> Nature 405: 482-485, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839546</a>] [<a href="https://doi.org/10.1038/35013100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839546">Bell and Felsenfeld (2000)</a> suggested that it controls imprinting of IGF2. The activity of this insulator is restricted to the maternal allele by specific DNA methylation of the paternal allele. <a href="#5" class="mim-tip-reference" title="Bell, A. C., Felsenfeld, G. <strong>Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene.</strong> Nature 405: 482-485, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839546</a>] [<a href="https://doi.org/10.1038/35013100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839546">Bell and Felsenfeld (2000)</a> concluded that DNA methylation can control gene expression by modulating enhancer access to the gene promoter through regulation of an enhancer boundary. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10839546+9851976" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The unmethylated imprinting-control region (ICR) acts as a chromatin boundary that blocks the interaction of IGF2 with enhancers that lie 3-prime of H19 (<a href="#32" class="mim-tip-reference" title="Webber, A., Ingram, R. S., Levorse, J. M., Tilghman, S. M. <strong>Location of enhancers is essential for imprinting of H19 and Igf2 genes.</strong> Nature 391: 711-715, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9490417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9490417</a>] [<a href="https://doi.org/10.1038/35655" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9490417">Webber et al., 1998</a>; <a href="#18" class="mim-tip-reference" title="Hark, A. T., Tilghman, S. M. <strong>Chromatin conformation of the H19 epigenetic mark.</strong> Hum. Molec. Genet. 7: 1979-1985, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9811943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9811943</a>] [<a href="https://doi.org/10.1093/hmg/7.12.1979" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9811943">Hark and Tilghman, 1998</a>). This enhancer-blocking activity would then be lost when the region was methylated, thereby allowing expression of IGF2 paternally. Using transgenic mice and tissue culture, <a href="#17" class="mim-tip-reference" title="Hark, A. T., Schoenherr, C. J., Katz, D. J., Ingram, R. S., Levrose, J. M., Tilghman, S. M. <strong>CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus.</strong> Nature 405: 486-489, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839547</a>] [<a href="https://doi.org/10.1038/35013106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839547">Hark et al. (2000)</a> demonstrated that the unmethylated ICRs from mouse and human H19 exhibit enhancer-blocking activity. They showed that CTCF binds to several sites in the unmethylated ICR that are essential for enhancer blocking. Consistent with this model, CTCF binding is abolished by DNA methylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9811943+10839547+9490417" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 the mouse, the H19 promoter area is methylated when transcription of the H19 gene is silent and unmethylated when it is active. <a href="#15" class="mim-tip-reference" title="Gao, Z.-H., Suppola, S., Liu, J., Heikkila, P., Janne, J., Voutilainen, R. <strong>Association of H19 promoter methylation with the expression of H19 and IGF-II genes in adrenocortical tumors.</strong> J. Clin. Endocr. Metab. 87: 1170-1176, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11889182/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11889182</a>] [<a href="https://doi.org/10.1210/jcem.87.3.8331" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11889182">Gao et al. (2002)</a> used PCR-based methylation analysis and bisulfite genomic sequencing to study the cytosine methylation status of the H19 promoter region in 16 normal adrenals and 30 pathologic adrenocortical samples. PCR-based analysis showed higher methylation status at 3 HpaII-cutting CpG sites of the H19 promoter in adrenocortical carcinomas and in a virilizing adenoma than in their adjacent normal adrenal tissues. Bisulfite genomic sequencing revealed a significantly higher mean degree of methylation at each of 12 CpG sites of the H19 promoter in adrenocortical carcinomas than in normal adrenals (P less than 0.01 for all sites) or adrenocortical adenomas (P less than 0.01, except P less than 0.05 for site 12 and P greater than 0.05 for site 11). The mean methylation degree of the 12 CpG sites was significantly higher in the adrenocortical carcinomas than in normal adrenals or adrenocortical adenomas (P less than 0.005). The mean methylation degree of the 12 H19 promoter CpG sites correlated negatively with H19 RNA levels but positively with IGF2 mRNA levels. Treatment with a cytosine methylation inhibitor, 5-aza-2-prime-deoxycytidine, increased H19 RNA expression, whereas it decreased IGF2 mRNA accumulation dose- and time-dependently (both P less than 0.005) and reduced cell proliferation to 10% in 7 days. The authors concluded that altered DNA methylation of the H19 promoter is involved in the abnormal expression of both H19 and IGF2 genes in human adrenocortical carcinomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11889182" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The most common constitutional abnormalities found in Beckwith-Wiedemann syndrome are epigenetic, involving abnormal methylation of either H19 or LIT1 (<a href="/entry/604115">604115</a>), both of which encode untranslated RNAs on 11p15. <a href="#11" class="mim-tip-reference" title="DeBaun, M. R., Niemitz, E. L., McNeil, D. E., Brandenburg, S. A., Lee, M. P., Feinberg, A. P. <strong>Epigenetic alterations of H19 and LIT1 distinguish patients with Beckwith-Wiedemann syndrome with cancer and birth defects.</strong> Am. J. Hum. Genet. 70: 604-611, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11813134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11813134</a>] [<a href="https://doi.org/10.1086/338934" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11813134">DeBaun et al. (2002)</a> hypothesized that different epigenetic alterations would be associated with specific phenotypes in BWS. To test this hypothesis, they performed a case-cohort study, using the BWS Registry. The cohort consisted of 92 patients with BWS who had had molecular analysis of both H19 and LIT1; these patients showed the same frequency of clinical phenotypes as those patients in the Registry from whom biologic samples were not available. The frequency of altered DNA methylation in H19 in patients with cancer was significantly higher, 56% (9/16), than the frequency in patients without cancer, 17% (13/76; P = 0.002), and cancer was not associated with LIT1 alterations. Furthermore, the frequency of altered DNA methylation of LIT1 in patients with midline abdominal wall defects and macrosomia was significantly higher, 65% (41/63) and 60% (46/77), respectively, than in patients without such defects, 34% (10/29) and 18% (2/11), respectively (P = 0.012 and P = 0.02, respectively). Additionally, paternal uniparental disomy of 11p15 was associated with hemihypertrophy (P = 0.003), cancer (P = 0.03), and hypoglycemia (P = 0.05). These results defined an epigenotype-phenotype relationship in BWS in which aberrant methylation of H19 and LIT1 and UPD are strongly associated with cancer risk and specific birth defects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11813134" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>For further information on the H19/IGF2-imprinting control region, see ICR1 (<a href="/entry/616186">616186</a>).</p>
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<p>The human H19 gene is 2.7 kb long and includes 4 small introns (<a href="#7" class="mim-tip-reference" title="Brannan, C. I., Dees, E. C., Ingram, R. S., Tilghman, S. M. <strong>The product of the H19 gene may function as an RNA.</strong> Molec. Cell. Biol. 10: 28-36, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1688465/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1688465</a>] [<a href="https://doi.org/10.1128/mcb.10.1.28-36.1990" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1688465">Brannan et al., 1990</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1688465" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Gao, W., Liu, M., Yang, Y., Yang, H., Liao, Q., Bai, Y., Li, Y., Li, D., Peng, C., Wang, Y.-L. <strong>The imprinted H19 gene regulates human placental trophoblast cell proliferation via encoding miR-675 that targets Nodal Modulator 1 (NOMO1).</strong> RNA Biol. 9: 1002-1010, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22832245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22832245</a>] [<a href="https://doi.org/10.4161/rna.20807" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22832245">Gao et al. (2012)</a> stated that exon 1 of the H19 gene contains MIR675. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22832245" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#22" class="mim-tip-reference" title="Leibovitch, M. P., Nguyen, V. C., Gross, M. S., Solhonne, B., Leibovitch, S. A., Bernheim, A. <strong>The human ASM (adult skeletal muscle) gene: expression and chromosomal assignment to 11p15.</strong> Biochem. Biophys. Res. Commun. 180: 1241-1250, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1953776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1953776</a>] [<a href="https://doi.org/10.1016/s0006-291x(05)81329-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1953776">Leibovitch et al. (1991)</a> mapped the human gene to 11p15 by a combination of somatic hybrid cell analysis and in situ hybridization. (D11S813E was the designation assigned by HGM11 (<a href="#25" class="mim-tip-reference" title="Nguyen, V. C., Leibovitch, M., Gross, M., Solhonne, B., Leibovitch, S. A., Bernheim, A. <strong>Assignment of ASM (adult skeletal muscle) to chromosome 11 (somatic hybrid cell analysis), region 11p15 (in situ hybridization). (Abstract)</strong> Cytogenet. Cell Genet. 58: 1968, 1991."None>Nguyen et al., 1991</a>).) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1953776" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 the mouse, the H19 gene is located on chromosome 7 in a region of conservation of synteny with human 11p (<a href="#20" class="mim-tip-reference" title="Jones, J. M., Meisler, M. H., Seldin, M. F., Lee, B. K., Eicher, E. M. <strong>Localization of insulin-2 (Ins-2) and the obesity mutant tubby (tub) to distinct regions of mouse chromosome 7.</strong> Genomics 14: 197-199, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1358794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1358794</a>] [<a href="https://doi.org/10.1016/s0888-7543(05)80308-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1358794">Jones et al., 1992</a>). Like the H19 gene, the Igf2 gene is imprinted in the mouse, although in the opposite parents, one paternally imprinted, the other maternally. <a href="#33" class="mim-tip-reference" title="Zemel, S., Bartolomei, M. S., Tilghman, S. M. <strong>Physical linkage of two mammalian imprinted genes, H19 and insulin-like growth factor 2.</strong> Nature Genet. 2: 61-65, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1303252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1303252</a>] [<a href="https://doi.org/10.1038/ng0992-61" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1303252">Zemel et al. (1992)</a> showed that the Igf2 gene lies about 90 kb 5-prime to H19, in the same transcriptional orientation. Based on similar pulsed field gel analysis, they showed that this physical proximity is conserved in humans. Both genes hybridized to a fragment of about 200 kb. <a href="#33" class="mim-tip-reference" title="Zemel, S., Bartolomei, M. S., Tilghman, S. M. <strong>Physical linkage of two mammalian imprinted genes, H19 and insulin-like growth factor 2.</strong> Nature Genet. 2: 61-65, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1303252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1303252</a>] [<a href="https://doi.org/10.1038/ng0992-61" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1303252">Zemel et al. (1992)</a> proposed a model to account for the imprinting of 2 linked genes in opposite directions, i.e., one (H19) being paternally imprinted and the other (IGF2) maternally imprinted. They pointed out that the IGF2/H19 domain is a candidate for the Beckwith-Wiedemann syndrome (BWS; <a href="/entry/130650">130650</a>) since the genes show imprinting and chimeric mouse embryos that are paternally disomic for distal mouse chromosome 7 show an overgrowth phenotype similar to that of BWS (<a href="#13" class="mim-tip-reference" title="Ferguson-Smith, A. C., Cattanach, B. M., Barton, S. C., Beechey, C. V., Surani, M. A. <strong>Embryological and molecular investigations of parental imprinting on mouse chromosome 7.</strong> Nature 351: 667-670, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2052093/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2052093</a>] [<a href="https://doi.org/10.1038/351667a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2052093">Ferguson-Smith et al., 1991</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1303252+2052093+1358794" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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See <a href="/entry/616186">616186</a> for information on the association of hypermethylation and variation in the H19/IGF2-imprinting control region and Beckwith-Wiedemann syndrome (BWS; <a href="/entry/130650">130650</a>).</p><p><strong><em>Silver-Russell Syndrome</em></strong></p><p>
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Hypermethylation of the H19 DMR, and subsequently of the H19 promoter region, is a major cause of the clinical features of gigantism and/or asymmetry seen in Beckwith-Wiedemann syndrome or in isolated hemihypertrophy (<a href="/entry/235000">235000</a>). <a href="#6" class="mim-tip-reference" title="Bliek, J., Terhal, P., van den Bogaard, M.-J., Maas, S., Hamel, B., Salieb-Beugelaar, G., Simon, M., Letteboer, T., van der Smagt, J., Kroes, H., Mannens, M. <strong>Hypomethylation of the H19 gene causes not only Silver-Russell syndrome (SRS) but also isolated asymmetry or an SRS-like phenotype.</strong> Am. J. Hum. Genet. 78: 604-614, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16532391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16532391</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16532391[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/502981" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16532391">Bliek et al. (2006)</a> demonstrated complete hypomethylation of the H19 promoter in 2 of 3 patients with the full clinical spectrum of Silver-Russell syndrome (SRS; <a href="/entry/180860">180860</a>), which shows clinical features opposite to those seen in patients with hypermethylation of this region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16532391" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>See <a href="/entry/616186">616186</a> for further information on the association of hypomethylation in the H19/IGF2-imprinting control region and Silver-Russell syndrome.</p><p><strong><em>Wilms Tumor</em></strong></p><p>
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See <a href="/entry/616186">616186</a> for information on the association of hypermethylation and variation in the H19/IGF2-imprinting control region and Wilms tumor (<a href="/entry/194071">194071</a>).</p>
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<p>Comparisons between eutherians and marsupials have suggested limited conservation of the molecular mechanisms that control genomic imprinting in mammals. <a href="#30" class="mim-tip-reference" title="Smits, G., Mungall, A. J., Griffiths-Jones, S., Smith, P., Beury, D., Matthews, L., Rogers, J., Pask, A. J., Shaw, G., VandeBerg, J. L., McCarrey, J. R., SAVOIR Consortium, Renfree, M. B., Reik, W., Dunham, I. <strong>Conservation of the H19 noncoding RNA and H19-IGF2 imprinting mechanism in therians.</strong> Nature Genet. 40: 971-976, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18587395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18587395</a>] [<a href="https://doi.org/10.1038/ng.168" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18587395">Smits et al. (2008)</a> studied the evolution of the imprinted IGF2-H19 locus in therians. Although marsupial orthologs of protein-coding exons were easily identified, the use of evolutionarily conserved regions and low-stringency Bl2seq comparisons was required to delineate a candidate H19 noncoding RNA sequence. The therian H19 orthologs showed miR675 and exon structure conservation, suggesting functional selection on both features. Transcription start site sequences and poly(A) signals are also conserved. As in eutherians, marsupial H19 is maternally expressed and paternal methylation upstream of the gene originates in the male germline, encompasses a CTCF insulator, and spreads somatically into the H19 gene. <a href="#30" class="mim-tip-reference" title="Smits, G., Mungall, A. J., Griffiths-Jones, S., Smith, P., Beury, D., Matthews, L., Rogers, J., Pask, A. J., Shaw, G., VandeBerg, J. L., McCarrey, J. R., SAVOIR Consortium, Renfree, M. B., Reik, W., Dunham, I. <strong>Conservation of the H19 noncoding RNA and H19-IGF2 imprinting mechanism in therians.</strong> Nature Genet. 40: 971-976, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18587395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18587395</a>] [<a href="https://doi.org/10.1038/ng.168" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18587395">Smits et al. (2008)</a> concluded that the conservation in all therians of the mechanism controlling imprinting of the IGF2-H19 locus suggests a sequential model of imprinting evolution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18587395" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#21" class="mim-tip-reference" title="Kono, T., Obata, Y., Wu, Q., Niwa, K., Ono, Y., Yamamoto, Y., Park, E. S., Seo, J.-S., Ogawa, H. <strong>Birth of parthenogenetic mice that can develop to adulthood.</strong> Nature 428: 860-864, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15103378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15103378</a>] [<a href="https://doi.org/10.1038/nature02402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15103378">Kono et al. (2004)</a> showed the development of a viable parthenogenetic mouse individual from a reconstructed oocyte containing 2 haploid sets of maternal genome derived from nongrowing and fully grown oocytes. This development was made possible by the appropriate expression of Igf2 and H19 genes with other imprinted genes, using mutant mice with a 13-kb deletion encompassing the H19 gene and its differentially methylated domain (<a href="#23" class="mim-tip-reference" title="Leighton, P. A., Ingram, R. S., Eggenschwiler, J., Efstratiadis, A., Tilghman, S. M. <strong>Disruption of imprinting caused by deletion of the H19 gene region in mice.</strong> Nature 375: 34-39, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7536897/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7536897</a>] [<a href="https://doi.org/10.1038/375034a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7536897">Leighton et al., 1995</a>), as the nongrowing oocyte donors. The 2 parthenotes that survived to term had marked reduction in aberrantly expressed genes. One parthenote developed to adulthood with the ability to reproduce offspring. <a href="#21" class="mim-tip-reference" title="Kono, T., Obata, Y., Wu, Q., Niwa, K., Ono, Y., Yamamoto, Y., Park, E. S., Seo, J.-S., Ogawa, H. <strong>Birth of parthenogenetic mice that can develop to adulthood.</strong> Nature 428: 860-864, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15103378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15103378</a>] [<a href="https://doi.org/10.1038/nature02402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15103378">Kono et al. (2004)</a> concluded that paternal imprinting prevents parthenogenesis, ensuring that the paternal contribution is obligatory for the descendant. Another startling observation of this study by <a href="#21" class="mim-tip-reference" title="Kono, T., Obata, Y., Wu, Q., Niwa, K., Ono, Y., Yamamoto, Y., Park, E. S., Seo, J.-S., Ogawa, H. <strong>Birth of parthenogenetic mice that can develop to adulthood.</strong> Nature 428: 860-864, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15103378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15103378</a>] [<a href="https://doi.org/10.1038/nature02402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15103378">Kono et al. (2004)</a> is that the appropriate expression of the IGF2 and H19 genes caused the modification of a wide range of genes and normal development in the surviving parthenotes. The better development may have led to altered signaling which then affected the expression of many other genes. However, the underlying mechanism was not clear. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15103378+7536897" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="1" class="mim-anchor"></a>
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<a id="Ariel1997" class="mim-anchor"></a>
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Ariel, I., Ayesh, S., Perlman, E. J., Pizov, G., Tanos, V., Schneider, T., Erdmann, V. A., Podeh, D., Komitowski, D., Quasem, A. S., de Groot, N., Hochberg, A.
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<strong>The product of the imprinted H19 gene is an oncofetal RNA.</strong>
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Molec. Path. 50: 34-44, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9208812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9208812</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9208812" 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/mp.50.1.34" target="_blank">Full Text</a>]
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Ariel, I., de Groot, N., Hochberg, A.
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<strong>Imprinted H19 gene expression in embryogenesis and human cancer: the oncofetal connection.</strong>
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Am. J. Med. Genet. 91: 46-50, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10751088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10751088</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10751088" 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/(sici)1096-8628(20000306)91:1<46::aid-ajmg8>3.0.co;2-i" target="_blank">Full Text</a>]
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Bartholdi, D., Krajewska-Walasek, M., Ounap, K., Gaspar, H., Chrzanowska, K. H., Ilyana, H., Kayserili, H., Lurie, I. W., Schinzel, A., Baumer, A.
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<strong>Epigenetic mutations of the imprinted IGF2-H19 domain in Silver-Russell syndrome (SRS): results from a large cohort of patients with SRS and SRS-like phenotypes. (Letter)</strong>
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J. Med. Genet. 46: 192-197, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19066168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19066168</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19066168" 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.2008.061820" target="_blank">Full Text</a>]
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Bartolomei, M. S., Zemel, S., Tilghman, S. M.
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<strong>Parental imprinting of the mouse H19 gene.</strong>
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Nature 351: 153-155, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1709450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1709450</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1709450" 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/10.1038/351153a0" target="_blank">Full Text</a>]
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Bell, A. C., Felsenfeld, G.
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<strong>Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene.</strong>
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Nature 405: 482-485, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839546</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10839546" 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/10.1038/35013100" target="_blank">Full Text</a>]
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Bliek, J., Terhal, P., van den Bogaard, M.-J., Maas, S., Hamel, B., Salieb-Beugelaar, G., Simon, M., Letteboer, T., van der Smagt, J., Kroes, H., Mannens, M.
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<strong>Hypomethylation of the H19 gene causes not only Silver-Russell syndrome (SRS) but also isolated asymmetry or an SRS-like phenotype.</strong>
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Am. J. Hum. Genet. 78: 604-614, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16532391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16532391</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16532391[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=16532391" 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/10.1086/502981" target="_blank">Full Text</a>]
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Brannan, C. I., Dees, E. C., Ingram, R. S., Tilghman, S. M.
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<strong>The product of the H19 gene may function as an RNA.</strong>
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Molec. Cell. Biol. 10: 28-36, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1688465/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1688465</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1688465" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1128/mcb.10.1.28-36.1990" target="_blank">Full Text</a>]
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Brunkow, M. E., Tilghman, S. M.
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<strong>Ectopic expression of the H19 gene in mice causes prenatal lethality.</strong>
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Genes Dev. 5: 1092-1101, 1991.
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[<a href="https://doi.org/10.1101/gad.5.6.1092" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1261/rna.351707" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/9.19.2885" target="_blank">Full Text</a>]
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</p>
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<a id="26" class="mim-anchor"></a>
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<a id="Pachnis1984" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Pachnis, V., Belayew, A., Tilghman, S. M.
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<strong>Locus unlinked to alpha-fetoprotein under the control of the murine raf and Rif genes.</strong>
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Proc. Nat. Acad. Sci. 81: 5523-5527, 1984.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6206499/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6206499</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6206499" 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.81.17.5523" target="_blank">Full Text</a>]
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</p>
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<a id="27" class="mim-anchor"></a>
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<a id="Pfeifer1996" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Pfeifer, K., Leighton, P. A., Tilghman, S. M.
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<strong>The structural H19 gene is required for transgene imprinting.</strong>
|
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Proc. Nat. Acad. Sci. 93: 13876-13883, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8943029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8943029</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=8943029[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=8943029" 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.93.24.13876" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="28" class="mim-anchor"></a>
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<a id="Rachmilewitz1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rachmilewitz, J., Goshen, R., Ariel, I., Schneider, T., de Groot, N., Hochberg, A.
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|
<strong>Parental imprinting of the human H19 gene.</strong>
|
|
FEBS Lett. 309: 25-28, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1380925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1380925</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1380925" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0014-5793(92)80731-u" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="29" class="mim-anchor"></a>
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<a id="Rainier1993" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rainier, S., Johnson, L. A., Dobry, C. J., Ping, A. J., Grundy, P. E., Feinberg, A. P.
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<strong>Relaxation of imprinted genes in human cancer.</strong>
|
|
Nature 362: 747-749, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8385745/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8385745</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8385745" 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/10.1038/362747a0" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="30" class="mim-anchor"></a>
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<a id="Smits2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Smits, G., Mungall, A. J., Griffiths-Jones, S., Smith, P., Beury, D., Matthews, L., Rogers, J., Pask, A. J., Shaw, G., VandeBerg, J. L., McCarrey, J. R., SAVOIR Consortium, Renfree, M. B., Reik, W., Dunham, I.
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<strong>Conservation of the H19 noncoding RNA and H19-IGF2 imprinting mechanism in therians.</strong>
|
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Nature Genet. 40: 971-976, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18587395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18587395</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18587395" 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.168" target="_blank">Full Text</a>]
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<a id="31" class="mim-anchor"></a>
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<a id="Thorvaldsen1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Thorvaldsen, J. L., Duran, K. L., Bartolomei, M. S.
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<strong>Deletion of the H19 differentially methylated domain results in loss of imprinted expression of H19 and Igf2.</strong>
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Genes Dev. 12: 3693-3702, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9851976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9851976</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9851976[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=9851976" 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/10.1101/gad.12.23.3693" target="_blank">Full Text</a>]
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<a id="32" class="mim-anchor"></a>
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<a id="Webber1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Webber, A., Ingram, R. S., Levorse, J. M., Tilghman, S. M.
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<strong>Location of enhancers is essential for imprinting of H19 and Igf2 genes.</strong>
|
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Nature 391: 711-715, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9490417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9490417</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9490417" 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/10.1038/35655" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="33" class="mim-anchor"></a>
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<a id="Zemel1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zemel, S., Bartolomei, M. S., Tilghman, S. M.
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<strong>Physical linkage of two mammalian imprinted genes, H19 and insulin-like growth factor 2.</strong>
|
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Nature Genet. 2: 61-65, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1303252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1303252</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1303252" 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/ng0992-61" target="_blank">Full Text</a>]
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<a id="34" class="mim-anchor"></a>
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<a id="Zhang1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, Y., Tycko, B.
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<strong>Monoallelic expression of the human H19 gene.</strong>
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Nature Genet. 1: 40-44, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1363808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1363808</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1363808" 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/ng0492-40" target="_blank">Full Text</a>]
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</ol>
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<br />
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<a id="contributors" class="mim-anchor"></a>
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Matthew B. Gross - updated : 1/15/2015
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz - updated : 11/4/2013<br>Ada Hamosh - updated : 10/3/2013<br>George E. Tiller - updated : 11/12/2010<br>Cassandra L. Kniffin - updated : 6/1/2009<br>Cassandra L. Kniffin - updated : 11/19/2008<br>Ada Hamosh - updated : 10/24/2008<br>Victor A. McKusick - updated : 11/21/2006<br>Ada Hamosh - updated : 5/26/2006<br>Victor A. McKusick - updated : 3/15/2006<br>George E. Tiller - updated : 2/17/2006<br>George E. Tiller - updated : 1/24/2006<br>Marla J. F. O'Neill - updated : 5/11/2005<br>George E. Tiller - updated : 5/9/2005<br>George E. Tiller - updated : 4/25/2005<br>George E. Tiller - updated : 3/3/2005<br>George E. Tiller - updated : 12/29/2004<br>Victor A. McKusick - updated : 9/27/2004<br>Victor A. McKusick - updated : 8/20/2004<br>Ada Hamosh - updated : 4/27/2004<br>Ada Hamosh - updated : 1/21/2004<br>John A. Phillips, III - updated : 7/29/2002<br>George E. Tiller - updated : 5/20/2002<br>Victor A. McKusick - updated : 3/21/2002<br>George E. Tiller - updated : 7/23/2001<br>George E. Tiller - updated : 5/23/2001<br>George E. Tiller - updated : 2/5/2001<br>Patti M. Sherman - updated : 7/14/2000<br>Ada Hamosh - updated : 5/24/2000<br>Victor A. McKusick - updated : 3/15/2000
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 1/9/1992
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</span>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 06/24/2016
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<div class="row collapse" id="mimCollapseEditHistory">
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<span class="mim-text-font">
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mgross : 1/15/2015<br>mgross : 1/15/2015<br>mgross : 11/4/2013<br>mcolton : 11/4/2013<br>alopez : 10/3/2013<br>terry : 4/4/2013<br>terry : 4/10/2012<br>wwang : 11/18/2010<br>terry : 11/12/2010<br>terry : 12/16/2009<br>carol : 12/1/2009<br>carol : 11/23/2009<br>wwang : 6/10/2009<br>ckniffin : 6/1/2009<br>alopez : 11/21/2008<br>alopez : 11/21/2008<br>ckniffin : 11/19/2008<br>alopez : 11/10/2008<br>terry : 10/24/2008<br>wwang : 4/25/2008<br>alopez : 11/27/2006<br>terry : 11/21/2006<br>alopez : 6/1/2006<br>alopez : 5/31/2006<br>terry : 5/26/2006<br>alopez : 3/21/2006<br>terry : 3/15/2006<br>wwang : 3/10/2006<br>terry : 2/17/2006<br>wwang : 1/24/2006<br>wwang : 5/11/2005<br>tkritzer : 5/9/2005<br>carol : 4/27/2005<br>tkritzer : 4/25/2005<br>alopez : 3/9/2005<br>terry : 3/3/2005<br>alopez : 12/29/2004<br>alopez : 9/30/2004<br>terry : 9/27/2004<br>tkritzer : 8/23/2004<br>terry : 8/20/2004<br>alopez : 4/28/2004<br>terry : 4/27/2004<br>alopez : 1/22/2004<br>terry : 1/21/2004<br>ckniffin : 8/26/2002<br>tkritzer : 7/29/2002<br>tkritzer : 7/29/2002<br>cwells : 5/30/2002<br>cwells : 5/20/2002<br>alopez : 3/27/2002<br>terry : 3/21/2002<br>cwells : 7/27/2001<br>cwells : 7/27/2001<br>cwells : 7/23/2001<br>cwells : 5/25/2001<br>cwells : 5/23/2001<br>cwells : 5/23/2001<br>cwells : 5/23/2001<br>cwells : 2/6/2001<br>cwells : 2/5/2001<br>cwells : 1/30/2001<br>terry : 10/6/2000<br>mcapotos : 8/1/2000<br>mcapotos : 7/27/2000<br>mcapotos : 7/24/2000<br>psherman : 7/14/2000<br>alopez : 5/24/2000<br>mcapotos : 3/29/2000<br>mcapotos : 3/28/2000<br>mcapotos : 3/28/2000<br>terry : 3/15/2000<br>carol : 4/21/1999<br>terry : 5/29/1998<br>alopez : 5/14/1998<br>terry : 1/23/1997<br>terry : 1/10/1997<br>mark : 5/2/1996<br>terry : 4/24/1996<br>mark : 7/20/1995<br>carol : 11/8/1993<br>carol : 9/24/1993<br>carol : 10/22/1992<br>carol : 10/13/1992<br>carol : 10/7/1992
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<h3>
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<span class="mim-font">
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<strong>*</strong> 103280
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<div>
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<h3>
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<span class="mim-font">
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H19, IMPRINTED MATERNALLY EXPRESSED NONCODING TRANSCRIPT; H19
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</h3>
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<div>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</p>
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<div>
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<h4>
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<span class="mim-font">
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LONG INTERGENIC NONCODING RNA H19<br />
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lincRNA H19<br />
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ADULT SKELETAL MUSCLE GENE; ASM<br />
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ASM1
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</span>
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</h4>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: H19</em></strong>
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</span>
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<strong>
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<em>
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Cytogenetic location: 11p15.5
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Genomic coordinates <span class="small">(GRCh38)</span> : 11:1,995,176-2,001,266 </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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</p>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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<p>The H19 gene encodes a sequence that is not translated and that is expressed exclusively from the maternal allele. The H19/IGF2-imprinting control region (ICR1; 616186), which is located just upstream of H19, coordinates expression of H19 and IGF2 (147470), which is expressed exclusively from the paternal allele (summary by Bartholdi et al., 2009). </p><p>The noncoding H19 RNA functions as the primary transcript for microRNA-675 (MIR675; 615509) (Cai and Cullen, 2007). </p>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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<p>Leibovitch et al. (1991) used a rat skeletal muscle probe originating from a rhabdomyosarcoma to isolate a cDNA probe from a human placental cDNA library. In the rat, while the corresponding mRNA and protein were not expressed in fetal muscle, an increasing accumulation of the corresponding mRNA and protein were observed during postnatal development of skeletal muscle, and this accumulation was maximal in adulthood. As no expression was found in any other tissue, the gene was referred to as the adult skeletal muscle (ASM) gene. A gene coding for an abundant fetal transcript in mice had been identified by Pachnis et al. (1984), who designated it H19. The H19 gene is expressed in a number of organs during a restricted period of fetal development, and in embryonal carcinoma cells after induction of differentiation (Bartolomei et al., 1991). The gene shows a restricted pattern of expression in adult tissues; expression is confined to skeletal and cardiac muscle. Leibovitch et al. (1991) presented evidence that the human H19 gene has a transcript that gives rise to a 29-kD protein. </p><p>Cai and Cullen (2007) determined that the 23-nucleotide MIR675 originates from nucleotides 1014 to 1036 of the noncoding human H19 transcript. </p>
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<strong>Gene Function</strong>
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<p><strong><em>Function of H19</em></strong></p><p>
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H19 is a developmentally regulated gene with putative tumor suppressor activity; it had been hypothesized that loss of H19 expression may be involved in Wilms tumorigenesis. Han et al. (1996) performed in situ hybridization analysis of H19 expression during normal rabbit development and in human atherosclerotic plaques. They found that H19 expression in developing skeletal and smooth muscles correlated with specific differentiation events in these tissues. Expression of H19 in skeletal muscle correlated with nonproliferative, actin-positive muscle cells. In the prenatal blood vessel, H19 expression was both temporally and spatially regulated with initial loss of expression in the inner smooth muscle layers adjacent to the lumen. Han et al. (1996) also identified H19-positive cells in adult atherosclerotic lesions, suggesting that these cells may recapitulate early developmental events. These results, along with the identification of the insulin family of growth factors as potent regulatory molecules for H19 expression, provided additional clues toward understanding the physiologic regulation and function of H19. </p><p>Genes expressed during embryogenesis, downregulated with tissue maturation and reexpressed in cancer, are designated oncofetal genes, and many of them are used as tumor markers. Ariel et al. (1997) showed oncofetal expression of H19 in human cancer. The study of H19 expression in testicular germ cell tumors of adolescents and young adults, which follow lines of differentiation of the conceptus, demonstrated dissociation between level of expression and monoallelic versus biallelic expression, which are 2 independent oncofetal characteristics of cancer. Ariel et al. (2000) reported that H19 is abundantly expressed in the fetal bladder mucosa and in carcinoma of the urinary bladder. It could be used as a marker of early recurrence and potentially as the basis for gene therapy. </p><p>Using real-time PCR, Dudek et al. (2010) found comparably high expression of Mir675, H19, and the master chondrocyte regulator Sox9 (608160) in adult mouse cartilage. Expression of H19, MIR675, SOX9, and collagen-2A1 (COL2A1; 120140) decreased with increasing passage number in chondrocytes cultured from juvenile and adult human articular cartilage. Depletion of SOX9 or H19 in human chondrocytes significantly reduced COL2A1 mRNA content and COL2A1 protein secretion. Overexpression of MIR675 reversed the effects of SOX9 or H19 depletion. Dudek et al. (2010) concluded that SOX9 functions through H19-derived MIR675 to increase COL2A1 expression in chondrocytes, possibly by inhibiting expression of a COL2A1 repressor. </p><p>NOMO1 (609157) antagonizes NODAL signaling (601265), which is critical for regulation of trophoblast cell growth. Gao et al. (2012) found that H19-derived MIR675 suppressed cell proliferation and promoted NODAL-mediated SMAD2 (601366) phosphorylation in human trophoblastic JEG-3 cells by directly inhibiting NOMO1 mRNA translation. Overexpression of NOMO1 reversed these effects. Knockdown of H19 or inhibition of MIR675 increased NOMO1 protein expression and promoted JEG-3 cell proliferation. </p><p><strong><em>Imprinting of H19</em></strong></p><p>
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Zhang and Tycko (1992) found restriction site polymorphisms in the human H19 gene and, by examination of the representation of these polymorphisms in cDNAs from fetal organs, demonstrated that H19 expression was largely or exclusively from a single allele. Expression of the WT1 gene (607102), which, like H19, maps to 11p and shows fetal expression, was found to have biallelic expression. In the context of previous studies of allelic losses in 11p15 in human embryonal tumors, the findings of Zhang and Tycko (1992) supported the possibility of single-step inactivation of monoallelically expressed growth-regulating genes in human oncogenesis. It was not determined in this study whether the expression was uniparental to indicate parental imprinting. The H19 gene and 2 other genes, IGF2 (147470) and IGF2 receptor (IGF2R; 147280), show monoallelic expression in mice. IGF2 is, like H19, located in 11p15. Zhang and Tycko (1992) commented that, if IGF2 also shows monoallelic expression, it may indicate that that region is a 'hotspot' for this phenomenon. </p><p>From the study of the androgenetic complete hydatidiform mole, Rachmilewitz et al. (1992) presented strong evidence of parental imprinting of the human H19 gene, with the maternally derived allele as the active one. Furthermore, they showed that the paternally derived allele of the IGF2 is expressed. Thus, the situation in the human is the same as that in the mouse. Rainier et al. (1993) found that both H19 and IGF2 show monoallelic expression in human tissues and that, as in mouse, H19 is expressed from the maternal allele and IGF2 from the paternal allele. In contrast, 69% of Wilms tumors not undergoing loss of heterozygosity at 11p showed biallelic expression of one or both genes, suggesting that relaxation or loss of imprinting may represent a new epigenetic mutational mechanism in carcinogenesis. </p><p>Mutter et al. (1993) found that normal gestations express H19 only from the maternal allele and express IGF2 from the paternal allele, whereas neither is expressed from the maternal genome of gynogenetic gestations, and both are expressed from the paternal genome of androgenetic gestations. Coexpression of H19 and IGF2 in the androgenetic tissues was in a single population of cells, mononuclear trophoblast--the same cell type expressing these genes in biparental placentas. These results demonstrated that a biparental genome may be required for expression of the reciprocal IGF2/H19 imprint. </p><p>In the mouse, the imprinted H19 gene, which encodes an untranslated RNA, lies at the end of a cluster of imprinted genes. Leighton et al. (1995) found that imprinting of the insulin-2 gene and the insulin-like growth factor-2 gene, which lie about 100 kb upstream of H19, can be disrupted by maternal inheritance of a targeted deletion of the H19 gene and its flanking sequence. Animals inheriting the H19 mutation from their mothers were 27% heavier than those inheriting from their fathers. Paternal inheritance of the disruption had no effect, which presumably reflects the normally silent state of the paternal gene. The somatic overgrowth of heterozygotes for the maternal deletion was attributed to a gain-of-function of the Igf2 gene rather than a loss of function of H19. </p><p>H19 is abundantly expressed in both extraembryonic and fetal tissues. Jinno et al. (1995) found that H19 is monoallelically (maternally) expressed in the human placenta after 10 weeks of gestation, whereas it is biallelically expressed at earlier stages. Regardless of H19 biallelic or monoallelic expression, IGF2 is monoallelically (paternally) expressed in the placenta. Furthermore, with in situ mRNA hybridization using placenta showing H19 biallelic and IGF2 monoallelic expression, they demonstrated that defined cell types simultaneously contained both H19 and IGF2 transcripts. Therefore, the reciprocal linkage of H19 and IGF2 expression demonstrated in Wilms tumors is not observed in placentas. Furthermore, Jinno et al. (1995) found that, unlike methylation analyses of the human H19 gene, the promoter region of the human H19 gene is hypomethylated at all stages of placental development. In contrast, allele-dependent methylation of the 3-prime portion of the gene increases with gestational age. </p><p>Pfeifer et al. (1996) stated that the H19 gene and its 5-prime-flanking sequence are required for the genomic imprinting of 2 paternally expressed genes in mice, Ins2 and Igf2, that lie 90 and 115 kb 5-prime to the H19 gene, respectively. Pfeifer et al. (1996) investigated the role of the H19 gene in its own imprinting by introducing a Mus spretus H19 gene into heterologous locations in the mouse genome. They found that multiple copies of the transgene were sufficient for its paternal silencing and DNA methylation. Replacing the H19 structural gene with a luciferase reporter gene resulted in loss of imprinting of the transgene; that is, high expression and low levels of DNA methylation were observed with both paternal and maternal inheritance. Removal of 701 bp at the 5-prime end of the structural H19 gene resulted in a similar loss of paternal-specific DNA methylation, arguing that those sequences are required for both the establishment and maintenance of the sperm-specific gametic mark. The M. spretus H19 transgene could not rescue the loss of IGF2 imprinting in trans in H19 deletion mice, implying a cis requirement for the H19 gene. In contrast to a previous report (Brunkow and Tilghman, 1991) in which overexpression of a marked H19 gene was a prenatal lethal, Pfeifer et al. (1996) found that expression of the M. spretus transgene had no deleterious effect, leading them to conclude that the 20-bp insertion in the marked gene created a neomorphic mutation. </p><p>Davis et al. (2000) analyzed the allelic methylation patterns of the maternally expressed, paternally methylated H19 gene during gametogenesis in the mouse embryo. Both parental alleles were devoid of methylation in male and female midgestation embryonic germ cells, suggesting that methylation imprints are erased in the germ cells prior to this time. In addition, the subsequent hypermethylation of the paternal and maternal alleles in the male germline occurred at different times. Although the paternal allele became hypermethylated during fetal stages, methylation of the maternal allele began during perinatal stages and continued postnatally through the onset of meiosis. The differential acquisition of methylation on the parental H19 alleles during gametogenesis may imply that the 2 unmethylated alleles can still be distinguished from each other. The authors concluded that in the absence of DNA methylation, other epigenetic mechanisms may maintain parental identity at the H19 locus during male germ cell development. </p><p>The expression of the IGF2 (147470) and H19 genes is imprinted. Although these neighboring genes share an enhancer, H19 is expressed only from the maternal allele, and IGF2 only from the paternally inherited allele. The region of paternal-specific methylation upstream of H19 appears to be the site of an epigenetic mark that is required for the imprinting of these genes. A deletion within this region results in loss of imprinting of both H19 and IGF2 (Thorvaldsen et al., 1998). Bell and Felsenfeld (2000) showed that this methylated region contains an element that blocks enhancer activity. The activity of this element is dependent upon the vertebrate enhancer-blocking protein CTCF (604167). Methylation of CpGs within the CTCF binding sites eliminates binding of CTCF in vitro, and deletion of these sites results in loss of enhancer-blocking activity in vivo, thereby allowing gene expression. This CTCF-dependent enhancer-blocking element acts as an insulator. Bell and Felsenfeld (2000) suggested that it controls imprinting of IGF2. The activity of this insulator is restricted to the maternal allele by specific DNA methylation of the paternal allele. Bell and Felsenfeld (2000) concluded that DNA methylation can control gene expression by modulating enhancer access to the gene promoter through regulation of an enhancer boundary. </p><p>The unmethylated imprinting-control region (ICR) acts as a chromatin boundary that blocks the interaction of IGF2 with enhancers that lie 3-prime of H19 (Webber et al., 1998; Hark and Tilghman, 1998). This enhancer-blocking activity would then be lost when the region was methylated, thereby allowing expression of IGF2 paternally. Using transgenic mice and tissue culture, Hark et al. (2000) demonstrated that the unmethylated ICRs from mouse and human H19 exhibit enhancer-blocking activity. They showed that CTCF binds to several sites in the unmethylated ICR that are essential for enhancer blocking. Consistent with this model, CTCF binding is abolished by DNA methylation. </p><p>In the mouse, the H19 promoter area is methylated when transcription of the H19 gene is silent and unmethylated when it is active. Gao et al. (2002) used PCR-based methylation analysis and bisulfite genomic sequencing to study the cytosine methylation status of the H19 promoter region in 16 normal adrenals and 30 pathologic adrenocortical samples. PCR-based analysis showed higher methylation status at 3 HpaII-cutting CpG sites of the H19 promoter in adrenocortical carcinomas and in a virilizing adenoma than in their adjacent normal adrenal tissues. Bisulfite genomic sequencing revealed a significantly higher mean degree of methylation at each of 12 CpG sites of the H19 promoter in adrenocortical carcinomas than in normal adrenals (P less than 0.01 for all sites) or adrenocortical adenomas (P less than 0.01, except P less than 0.05 for site 12 and P greater than 0.05 for site 11). The mean methylation degree of the 12 CpG sites was significantly higher in the adrenocortical carcinomas than in normal adrenals or adrenocortical adenomas (P less than 0.005). The mean methylation degree of the 12 H19 promoter CpG sites correlated negatively with H19 RNA levels but positively with IGF2 mRNA levels. Treatment with a cytosine methylation inhibitor, 5-aza-2-prime-deoxycytidine, increased H19 RNA expression, whereas it decreased IGF2 mRNA accumulation dose- and time-dependently (both P less than 0.005) and reduced cell proliferation to 10% in 7 days. The authors concluded that altered DNA methylation of the H19 promoter is involved in the abnormal expression of both H19 and IGF2 genes in human adrenocortical carcinomas. </p><p>The most common constitutional abnormalities found in Beckwith-Wiedemann syndrome are epigenetic, involving abnormal methylation of either H19 or LIT1 (604115), both of which encode untranslated RNAs on 11p15. DeBaun et al. (2002) hypothesized that different epigenetic alterations would be associated with specific phenotypes in BWS. To test this hypothesis, they performed a case-cohort study, using the BWS Registry. The cohort consisted of 92 patients with BWS who had had molecular analysis of both H19 and LIT1; these patients showed the same frequency of clinical phenotypes as those patients in the Registry from whom biologic samples were not available. The frequency of altered DNA methylation in H19 in patients with cancer was significantly higher, 56% (9/16), than the frequency in patients without cancer, 17% (13/76; P = 0.002), and cancer was not associated with LIT1 alterations. Furthermore, the frequency of altered DNA methylation of LIT1 in patients with midline abdominal wall defects and macrosomia was significantly higher, 65% (41/63) and 60% (46/77), respectively, than in patients without such defects, 34% (10/29) and 18% (2/11), respectively (P = 0.012 and P = 0.02, respectively). Additionally, paternal uniparental disomy of 11p15 was associated with hemihypertrophy (P = 0.003), cancer (P = 0.03), and hypoglycemia (P = 0.05). These results defined an epigenotype-phenotype relationship in BWS in which aberrant methylation of H19 and LIT1 and UPD are strongly associated with cancer risk and specific birth defects. </p><p>For further information on the H19/IGF2-imprinting control region, see ICR1 (616186).</p>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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<p>The human H19 gene is 2.7 kb long and includes 4 small introns (Brannan et al., 1990). </p><p>Gao et al. (2012) stated that exon 1 of the H19 gene contains MIR675. </p>
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<span class="mim-font">
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<strong>Mapping</strong>
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<span class="mim-text-font">
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<p>Leibovitch et al. (1991) mapped the human gene to 11p15 by a combination of somatic hybrid cell analysis and in situ hybridization. (D11S813E was the designation assigned by HGM11 (Nguyen et al., 1991).) </p><p>In the mouse, the H19 gene is located on chromosome 7 in a region of conservation of synteny with human 11p (Jones et al., 1992). Like the H19 gene, the Igf2 gene is imprinted in the mouse, although in the opposite parents, one paternally imprinted, the other maternally. Zemel et al. (1992) showed that the Igf2 gene lies about 90 kb 5-prime to H19, in the same transcriptional orientation. Based on similar pulsed field gel analysis, they showed that this physical proximity is conserved in humans. Both genes hybridized to a fragment of about 200 kb. Zemel et al. (1992) proposed a model to account for the imprinting of 2 linked genes in opposite directions, i.e., one (H19) being paternally imprinted and the other (IGF2) maternally imprinted. They pointed out that the IGF2/H19 domain is a candidate for the Beckwith-Wiedemann syndrome (BWS; 130650) since the genes show imprinting and chimeric mouse embryos that are paternally disomic for distal mouse chromosome 7 show an overgrowth phenotype similar to that of BWS (Ferguson-Smith et al., 1991). </p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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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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See 616186 for information on the association of hypermethylation and variation in the H19/IGF2-imprinting control region and Beckwith-Wiedemann syndrome (BWS; 130650).</p><p><strong><em>Silver-Russell Syndrome</em></strong></p><p>
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Hypermethylation of the H19 DMR, and subsequently of the H19 promoter region, is a major cause of the clinical features of gigantism and/or asymmetry seen in Beckwith-Wiedemann syndrome or in isolated hemihypertrophy (235000). Bliek et al. (2006) demonstrated complete hypomethylation of the H19 promoter in 2 of 3 patients with the full clinical spectrum of Silver-Russell syndrome (SRS; 180860), which shows clinical features opposite to those seen in patients with hypermethylation of this region. </p><p>See 616186 for further information on the association of hypomethylation in the H19/IGF2-imprinting control region and Silver-Russell syndrome.</p><p><strong><em>Wilms Tumor</em></strong></p><p>
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See 616186 for information on the association of hypermethylation and variation in the H19/IGF2-imprinting control region and Wilms tumor (194071).</p>
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<span class="mim-font">
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<strong>Evolution</strong>
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<span class="mim-text-font">
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<p>Comparisons between eutherians and marsupials have suggested limited conservation of the molecular mechanisms that control genomic imprinting in mammals. Smits et al. (2008) studied the evolution of the imprinted IGF2-H19 locus in therians. Although marsupial orthologs of protein-coding exons were easily identified, the use of evolutionarily conserved regions and low-stringency Bl2seq comparisons was required to delineate a candidate H19 noncoding RNA sequence. The therian H19 orthologs showed miR675 and exon structure conservation, suggesting functional selection on both features. Transcription start site sequences and poly(A) signals are also conserved. As in eutherians, marsupial H19 is maternally expressed and paternal methylation upstream of the gene originates in the male germline, encompasses a CTCF insulator, and spreads somatically into the H19 gene. Smits et al. (2008) concluded that the conservation in all therians of the mechanism controlling imprinting of the IGF2-H19 locus suggests a sequential model of imprinting evolution. </p>
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<strong>Animal Model</strong>
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<p>Kono et al. (2004) showed the development of a viable parthenogenetic mouse individual from a reconstructed oocyte containing 2 haploid sets of maternal genome derived from nongrowing and fully grown oocytes. This development was made possible by the appropriate expression of Igf2 and H19 genes with other imprinted genes, using mutant mice with a 13-kb deletion encompassing the H19 gene and its differentially methylated domain (Leighton et al., 1995), as the nongrowing oocyte donors. The 2 parthenotes that survived to term had marked reduction in aberrantly expressed genes. One parthenote developed to adulthood with the ability to reproduce offspring. Kono et al. (2004) concluded that paternal imprinting prevents parthenogenesis, ensuring that the paternal contribution is obligatory for the descendant. Another startling observation of this study by Kono et al. (2004) is that the appropriate expression of the IGF2 and H19 genes caused the modification of a wide range of genes and normal development in the surviving parthenotes. The better development may have led to altered signaling which then affected the expression of many other genes. However, the underlying mechanism was not clear. </p>
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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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<p />
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</div>
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<div>
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<ol>
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<p class="mim-text-font">
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Ariel, I., Ayesh, S., Perlman, E. J., Pizov, G., Tanos, V., Schneider, T., Erdmann, V. A., Podeh, D., Komitowski, D., Quasem, A. S., de Groot, N., Hochberg, A.
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<strong>The product of the imprinted H19 gene is an oncofetal RNA.</strong>
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Molec. Path. 50: 34-44, 1997.
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[PubMed: 9208812]
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[Full Text: https://doi.org/10.1136/mp.50.1.34]
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</li>
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<li>
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<p class="mim-text-font">
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Ariel, I., de Groot, N., Hochberg, A.
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<strong>Imprinted H19 gene expression in embryogenesis and human cancer: the oncofetal connection.</strong>
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Am. J. Med. Genet. 91: 46-50, 2000.
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[PubMed: 10751088]
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[Full Text: https://doi.org/10.1002/(sici)1096-8628(20000306)91:1<46::aid-ajmg8>3.0.co;2-i]
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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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Bartholdi, D., Krajewska-Walasek, M., Ounap, K., Gaspar, H., Chrzanowska, K. H., Ilyana, H., Kayserili, H., Lurie, I. W., Schinzel, A., Baumer, A.
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<strong>Epigenetic mutations of the imprinted IGF2-H19 domain in Silver-Russell syndrome (SRS): results from a large cohort of patients with SRS and SRS-like phenotypes. (Letter)</strong>
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J. Med. Genet. 46: 192-197, 2009.
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[PubMed: 19066168]
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[Full Text: https://doi.org/10.1136/jmg.2008.061820]
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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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Bartolomei, M. S., Zemel, S., Tilghman, S. M.
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<strong>Parental imprinting of the mouse H19 gene.</strong>
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Nature 351: 153-155, 1991.
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[PubMed: 1709450]
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[Full Text: https://doi.org/10.1038/351153a0]
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</p>
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<p class="mim-text-font">
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Bell, A. C., Felsenfeld, G.
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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">
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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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Matthew B. Gross - updated : 1/15/2015<br>Patricia A. Hartz - updated : 11/4/2013<br>Ada Hamosh - updated : 10/3/2013<br>George E. Tiller - updated : 11/12/2010<br>Cassandra L. Kniffin - updated : 6/1/2009<br>Cassandra L. Kniffin - updated : 11/19/2008<br>Ada Hamosh - updated : 10/24/2008<br>Victor A. McKusick - updated : 11/21/2006<br>Ada Hamosh - updated : 5/26/2006<br>Victor A. McKusick - updated : 3/15/2006<br>George E. Tiller - updated : 2/17/2006<br>George E. Tiller - updated : 1/24/2006<br>Marla J. F. O'Neill - updated : 5/11/2005<br>George E. Tiller - updated : 5/9/2005<br>George E. Tiller - updated : 4/25/2005<br>George E. Tiller - updated : 3/3/2005<br>George E. Tiller - updated : 12/29/2004<br>Victor A. McKusick - updated : 9/27/2004<br>Victor A. McKusick - updated : 8/20/2004<br>Ada Hamosh - updated : 4/27/2004<br>Ada Hamosh - updated : 1/21/2004<br>John A. Phillips, III - updated : 7/29/2002<br>George E. Tiller - updated : 5/20/2002<br>Victor A. McKusick - updated : 3/21/2002<br>George E. Tiller - updated : 7/23/2001<br>George E. Tiller - updated : 5/23/2001<br>George E. Tiller - updated : 2/5/2001<br>Patti M. Sherman - updated : 7/14/2000<br>Ada Hamosh - updated : 5/24/2000<br>Victor A. McKusick - updated : 3/15/2000
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</span>
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</div>
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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">
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Creation Date:
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 1/9/1992
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